Publications by authors named "Jonathan Posner"

110 Publications

Major depression, temperament, and social support as psychosocial mechanisms of the intergenerational transmission of parenting styles.

Dev Psychopathol 2021 Jun 8:1-15. Epub 2021 Jun 8.

Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

In this three-generation longitudinal study of familial depression, we investigated the continuity of parenting styles, and major depressive disorder (MDD), temperament, and social support during childrearing as potential mechanisms. Each generation independently completed the Parental Bonding Instrument (PBI), measuring individuals' experiences of care and overprotection received from parents during childhood. MDD was assessed prospectively, up to 38 years, using the semi-structured Schedule for Affective Disorders and Schizophrenia (SADS). Social support and temperament were assessed using the Social Adjustment Scale - Self-Report (SAS-SR) and Dimensions of Temperament Scales - Revised, respectively. We first assessed transmission of parenting styles in the generation 1 to generation 2 cycle (G1→G2), including 133 G1 and their 229 G2 children (367 pairs), and found continuity of both care and overprotection. G1 MDD accounted for the association between G1→G2 experiences of care, and G1 social support and temperament moderated the transmission of overprotection. The findings were largely similar when examining these psychosocial mechanisms in 111 G2 and their spouses (G2+S) and their 136 children (G3) (a total of 223 pairs). Finally, in a subsample of families with three successive generations (G1→G2→G3), G2 experiences of overprotection accounted for the association between G1→G3 experiences of overprotection. The results of this study highlight the roles of MDD, temperament, and social support in the intergenerational continuity of parenting, which should be considered in interventions to "break the cycle" of poor parenting practices across generations.
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http://dx.doi.org/10.1017/S0954579421000420DOI Listing
June 2021

Major depression, temperament, and social support as psychosocial mechanisms of the intergenerational transmission of parenting styles.

Dev Psychopathol 2021 Jun 8:1-15. Epub 2021 Jun 8.

Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

In this three-generation longitudinal study of familial depression, we investigated the continuity of parenting styles, and major depressive disorder (MDD), temperament, and social support during childrearing as potential mechanisms. Each generation independently completed the Parental Bonding Instrument (PBI), measuring individuals' experiences of care and overprotection received from parents during childhood. MDD was assessed prospectively, up to 38 years, using the semi-structured Schedule for Affective Disorders and Schizophrenia (SADS). Social support and temperament were assessed using the Social Adjustment Scale - Self-Report (SAS-SR) and Dimensions of Temperament Scales - Revised, respectively. We first assessed transmission of parenting styles in the generation 1 to generation 2 cycle (G1→G2), including 133 G1 and their 229 G2 children (367 pairs), and found continuity of both care and overprotection. G1 MDD accounted for the association between G1→G2 experiences of care, and G1 social support and temperament moderated the transmission of overprotection. The findings were largely similar when examining these psychosocial mechanisms in 111 G2 and their spouses (G2+S) and their 136 children (G3) (a total of 223 pairs). Finally, in a subsample of families with three successive generations (G1→G2→G3), G2 experiences of overprotection accounted for the association between G1→G3 experiences of overprotection. The results of this study highlight the roles of MDD, temperament, and social support in the intergenerational continuity of parenting, which should be considered in interventions to "break the cycle" of poor parenting practices across generations.
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http://dx.doi.org/10.1017/S0954579421000420DOI Listing
June 2021

Prenatal environmental tobacco smoke exposure alters children's cognitive control circuitry: A preliminary study.

Environ Int 2021 May 6;155:106516. Epub 2021 May 6.

The Division of Child and Adolescent Psychiatry in the Department of Psychiatry, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.

Background And Objectives: Prenatal exposure to environmental tobacco smoke (ETS) is associated with increased attention problems in children, however, the effects of such exposure on children's brain structure and function have not been studied. Herein, we probed effects of prenatal ETS on children's cognitive control circuitry and behavior.

Methods: Forty-one children (7-9 years) recruited from a prospective longitudinal birth cohort of non-smoking mothers completed structural and task-functional magnetic resonance imaging to evaluate effects of maternal ETS exposure, measured by maternal prenatal urinary cotinine. Attention problems and externalizing behaviors were measured by parent report on the Child Behavior Checklist.

Results: Compared to non-exposed children, exposed children had smaller left and right thalamic and inferior frontal gyrus (IFG) volumes, with large effect sizes (p-FDR < .05, Cohen's D range from 0.79 to 1.07), and increased activation in IFG during the resolution of cognitive conflict measured with the Simon Spatial Incompatibility Task (38 voxels; peak t(25) = 5.25, p-FWE = .005). Reduced thalamic volume was associated with increased IFG activation and attention problems, reflecting poor cognitive control. Mediation analyses showed a trend toward left thalamic volume mediating the association between exposure and attention problems (p = .05).

Conclusions: Our findings suggest that maternal ETS exposure during pregnancy has deleterious effects on the structure and function of cognitive control circuitry which in turn affects attentional capacity in school-age children. These findings are consistent with prior findings documenting the effects of active maternal smoking on chidlren's neurodevleoment, pointing to the neurotixicity of nicotine regardless of exposure pathway.
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http://dx.doi.org/10.1016/j.envint.2021.106516DOI Listing
May 2021

HIV detection from human serum with paper-based isotachophoretic RNA extraction and reverse transcription recombinase polymerase amplification.

Analyst 2021 May;146(9):2851-2861

Department of Mechanical Engineering, University of Washington, Seattle, USA. and Department of Chemical Engineering, University of Washington, Seattle, USA and Family Medicine, School of Medicine, University of Washington, Seattle, USA.

The number of people living with HIV continues to increase with the current total near 38 million, of which about 26 million are receiving antiretroviral therapy (ART). These treatment regimens are highly effective when properly managed, requiring routine viral load monitoring to assess successful viral suppression. Efforts to expand access by decentralizing HIV nucleic acid testing in low- and middle-income countries (LMICs) has been hampered by the cost and complexity of current tests. Sample preparation of blood samples has traditionally relied on cumbersome RNA extraction methods, and it continues to be a key bottleneck for developing low-cost POC nucleic acid tests. We present a microfluidic paper-based analytical device (μPAD) for extracting RNA and detecting HIV in serum, leveraging low-cost materials, simple buffers, and an electric field. We detect HIV virions and MS2 bacteriophage internal control in human serum using a novel lysis and RNase inactivation method, paper-based isotachophoresis (ITP) for RNA extraction, and duplexed reverse transcription recombinase polymerase amplification (RT-RPA) for nucleic acid amplification. We design a specialized ITP system to extract and concentrate RNA, while excluding harsh reagents used for lysis and RNase inactivation. We found the ITP μPAD can extract and purify 5000 HIV RNA copies per mL of serum. We then demonstrate detection of HIV virions and MS2 bacteriophage in human serum within 45-minutes.
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http://dx.doi.org/10.1039/d0an02483jDOI Listing
May 2021

Current state of commercial point-of-care nucleic acid tests for infectious diseases.

Analyst 2021 Apr 7;146(8):2449-2462. Epub 2021 Apr 7.

Department of Mechanical Engineering, University of Washington, USA.

The COVID-19 pandemic has put the spotlight on the urgent need for integrated nucleic acid tests (NATs) for infectious diseases, especially those that can be used near patient ("point-of-care", POC), with rapid results and low cost, but without sacrificing sensitivity or specificity of gold standard PCR tests. In the US, the Clinical Laboratory Improvement Amendments Certificate of Waiver (CLIA-waiver) is mandated by the Food and Drug Administration (FDA) and designated to any laboratory testing with high simplicity and low risk for error, suitable for application in the POC. Since the first issuance of CLIA-waiver to Abbot's ID NOW Influenza A&B in 2015, many more NAT systems have been developed, received the CLIA-waiver in the US or World Health Organization (WHO)'s pre-qualification, and deployed to the front line of infectious disease detection. This review highlights the regulatory process for FDA and WHO in evaluating these NATs and the technology innovation of existing CLIA-waived systems. Understanding the technical advancement and challenges, unmet needs, and the trends of commercialization facilitated through the regulatory processes will help pave the foundation for future development and technology transfer from research to the market place.
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http://dx.doi.org/10.1039/d0an01988gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139840PMC
April 2021

Association of Multigenerational Family History of Depression With Lifetime Depressive and Other Psychiatric Disorders in Children: Results from the Adolescent Brain Cognitive Development (ABCD) Study.

JAMA Psychiatry 2021 Apr 21. Epub 2021 Apr 21.

Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.

Importance: Three-generation family studies of depression have established added risk of psychopathology for offspring with 2 previous generations affected with depression compared with 1 or none. Because of their rigorous methodology, there are few of these studies, and existing studies are limited by sample sizes. Consequently, the 3-generation family risk paradigm established in family studies can be a critical neuropsychiatric tool if similar transmission patterns are reliably demonstrated with the family history method.

Objective: To examine the association of multigenerational family history of depression with lifetime depressive disorders and other psychopathology in children.

Design, Setting, And Participants: In this analysis of the Adolescent Brain Cognitive Development (ABCD) study data, retrospective, cross-sectional reports on psychiatric functioning among 11 200 children (generation 3 [G3]) and parent reports on parents' (G2) and grandparents' (G1) depression histories were analyzed. The ABCD study sampling weights were used for generalized estimating equation models and descriptive analyses. Data were collected from September 2016 to November 2018, and data were analyzed from July to November 2020.

Main Outcomes And Measures: Four risk categories were created, reflecting how many prior generations had history of depression: (1) neither G1 nor G2 (G1-/G2-), (2) only G1 (G1+/G2-), (3) only G2 (G1-/G2+), and (4) both G1 and G2 (G1+/G2+). Child lifetime prevalence and relative risks of psychiatric disorders were based on child and caregiver reports and grouped according to familial risk category derived from G1 and G2 depression history.

Results: Among 11 200 included children, 5355 (47.8%) were female, and the mean (SD) age was 9.9 (0.6) years. By parent reports, the weighted prevalence of depressive disorder among children was 3.8% (95% CI, 3.2-4.3) for G1-/G2- children, 5.5% (95% CI, 4.3-7.1) for G1+/G2- children, 10.4% (95% CI, 8.6-12.6) for G1-/G2+ children, and 13.3% (95% CI, 11.6-15.2) for G1+/G2+ children (Cochran-Armitage trend = 243.77; P < .001). The weighted suicidal behavior prevalence among children was 5.0% (95% CI, 4.5-5.6) for G1-/G2- children, 7.2% (95% CI, 5.8-8.9) for G1+/G2- children, 12.1% (95% CI, 10.1-14.4) for G1-/G2+ children, and 15.0% (95% CI, 13.2-17.0) for G1+/G2+ children (Cochran-Armitage trend = 188.66; P < .001). By child reports, the weighted prevalence of depressive disorder was 4.8% (95% CI, 4.3-5.5) for G1-/G2- children, 4.3% (95% CI, 3.2-5.7) for G1+/G2- children, 6.3% (95% CI, 4.9-8.1) for G1-/G2+ children, and 7.0% (95% CI, 5.8-8.5) for G1+/G2+ children (Cochran-Armitage trend = 9.01; P = .002), and the weighted prevalence of suicidal behaviors was 7.4% (95% CI, 6.7-8.2) for G1-/G2- children, 7.0% (95% CI, 5.6-8.6) for G1+/G2- children, 9.8% (95% CI, 8.1-12.0) for G1-/G2+ children, and 13.8% (95% CI, 12.1-15.8) for G1+/G2+ children (Cochran-Armitage trend = 46.69; P < .001). Similar patterns were observed for other disorders for both parent and child reports and across sex, socioeconomic status, and race/ethnicity.

Conclusions And Relevance: In this study, having multiple prior affected generations was associated with increased risk of childhood psychopathology. Furthermore, these findings were detectable even at prepubertal ages and existed in diverse racial/ethnic and socioeconomic groups. Clinically, they underscore the need for screening for family history in pediatric settings and highlight implications for biological research with homogenous subgroups using magnetic resonance imaging or genetic analyses.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060885PMC
April 2021

Pilot evaluation of an enzymatic assay for rapid measurement of antiretroviral drug concentrations.

Virol J 2021 Apr 15;18(1):77. Epub 2021 Apr 15.

Department of Global Health, Schools of Medicine and Public Health, University of Washington, Seattle, USA.

Objective: Maintaining adequate drug adherence is crucial to ensure the HIV prevention benefits of pre-exposure prophylaxis (PrEP). We developed an enzymatic assay for rapidly measuring tenofovir-diphosphate (TFV-DP) concentrations-a metabolite that indicates long-term PrEP adherence.

Setting: The study was conducted at the Madison HIV Clinic at Harborview Medical Center in Seattle.

Methods: We enrolled adults receiving standard oral PrEP, and individuals not receiving any antiretrovirals. We measured TFV-DP concentrations in diluted whole blood using our novel REverSe TRanscrIptase Chain Termination (RESTRICT) assay, based on inhibition of HIV reverse transcriptase (RT) enzyme. Blood samples were diluted in water, DNA templates, nucleotides, RT, and intercalating dye added, and results measured with a fluorescence reader-stronger fluorescence indicated higher RT activity. We compared RESTRICT assay results to TFV-DP concentrations from matched dried blood spot samples measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) using ≥ 700 fmol/punch TFV-DP as a threshold for adequate adherence (≥ 4 doses/week).

Results: Among 18 adults enrolled, 4 of 7 participants receiving PrEP had TFV-DP levels ≥ 700 fmol/punch by LC-MS/MS. RESTRICT fluorescence correlated with LC-MS/MS measurements (r = - 0.845, p < 0.0001). Median fluorescence was 93.3 (95% confidence interval [CI] 90.9 to 114) for samples < 700 fmol/punch and 54.4 (CI 38.0 to 72.0) for samples ≥ 700 fmol/punch. When calibrated to an a priori defined threshold of 82.7, RESTRICT distinguished both groups with 100% sensitivity and 92.9% specificity.

Conclusions: This novel enzymatic assay for measuring HIV reverse transcriptase activity may be suitable for distinguishing TFV-DP concentrations in blood that correspond to protective PrEP adherence.
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http://dx.doi.org/10.1186/s12985-021-01543-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048217PMC
April 2021

Differential Association of Spirituality and Religiosity With Rumination: Implications for the Treatment of Depression.

J Nerv Ment Dis 2021 May;209(5):370-377

Division of Translational Epidemiology, New York State Psychiatric Institute.

Abstract: Recent studies have shown that religiosity (R) is associated with lower rates of depression, whereas spirituality (S) is associated with higher rates. Rumination has also been associated with higher rates of depression. Some have hypothesized that rumination mediates the differential association of religiosity and spirituality with depression. We empirically test this hypothesis in a longitudinal, multigenerational sample through associations between rumination and depression, R/S and depression, and R/S and rumination. Cross-sectionally, total rumination scores were predicted by spirituality (standardized β = 0.13; 95% confidence interval [CI], 0.00-0.26), with subscale (reflection, depression, and brooding) standardized betas ranging from 0.11 to 0.15 (95% CI, -0.03 to -0.29). Cross-sectionally, rumination was not predicted by religiosity. Longitudinally, and consistent with previous findings, religiosity, but not spirituality, predicted reduced depressive symptoms (standardized β = -0.3; 95% CI, -0.58 to -0.01). The association between spirituality and rumination was driven by millennials. Psychotherapies that target rumination for depression might therefore be especially effective in the millennial demographic.
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http://dx.doi.org/10.1097/NMD.0000000000001306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041060PMC
May 2021

Chemokinesis-driven accumulation of active colloids in low-mobility regions of fuel gradients.

Sci Rep 2021 Feb 26;11(1):4785. Epub 2021 Feb 26.

Department of Mechanical Engineering, University of Washington, Seattle, WA, USA.

Many motile cells exhibit migratory behaviors, such as chemotaxis (motion up or down a chemical gradient) or chemokinesis (dependence of speed on chemical concentration), which enable them to carry out vital functions including immune response, egg fertilization, and predator evasion. These have inspired researchers to develop self-propelled colloidal analogues to biological microswimmers, known as active colloids, that perform similar feats. Here, we study the behavior of half-platinum half-gold (Pt/Au) self-propelled rods in antiparallel gradients of hydrogen peroxide fuel and salt, which tend to increase and decrease the rods' speed, respectively. Brownian Dynamics simulations, a Fokker-Planck theoretical model, and experiments demonstrate that, at steady state, the rods accumulate in low-speed (salt-rich, peroxide-poor) regions not because of chemotaxis, but because of chemokinesis. Chemokinesis is distinct from chemotaxis in that no directional sensing or reorientation capabilities are required. The agreement between simulations, model, and experiments bolsters the role of chemokinesis in this system. This work suggests a novel strategy of exploiting chemokinesis to effect accumulation of motile colloids in desired areas.
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http://dx.doi.org/10.1038/s41598-021-83963-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910604PMC
February 2021

Dissociating disorders of depression, anxiety, and their comorbidity with measures of emotional processing: A joint analysis of visual brain potentials and auditory perceptual asymmetries.

Biol Psychol 2021 03 5;160:108040. Epub 2021 Feb 5.

New York State Psychiatric Institute, New York, NY, USA; Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

In a multigenerational study of families at risk for depression, individuals with a lifetime history of depression had: 1) abnormal perceptual asymmetry (PA; smaller left ear/right hemisphere [RH] advantage) in a dichotic emotion recognition task, and 2) reduced RH late positive potential (P3) during an emotional hemifield task. We used standardized difference scores for processing auditory (PA sad-neutral) and visual (P3 negative-neutral) stimuli for 112 participants (52 men) in a logistic regression to predict history of depression, anxiety or comorbidity of both. Whereas comorbidity was separately predicted by reduced PA (OR = 0.527, p = .042) or P3 (OR = 0.457, p = .013) alone, an interaction between PA and P3 (OR = 2.499, p = .011) predicted depressive disorder. Follow-up analyses revealed increased probability of depression at low (lack of emotional differentiation) and high (heightened reactivity to negative stimuli) levels of both predictors. Findings suggest that reduced or heightened right-lateralized emotional responsivity to negative stimuli may be uniquely associated with depression.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108646PMC
March 2021

Frontoparietal and default mode network connectivity varies with age and intelligence.

Dev Cogn Neurosci 2021 Apr 27;48:100928. Epub 2021 Jan 27.

The Division of Child and Adolescent Psychiatry, Columbia University Irving Medical Center, United States. Electronic address:

Background: Anticorrelated resting state connectivity between task-positive and task-negative networks in adults supports flexible shifting between externally focused attention and internal thought. Findings suggest that children show positive correlations between task-positive (frontoparietal; FP) and task-negative (default mode; DMN) networks. FP-DMN connectivity also associates with intellectual functioning across the lifespan. We investigated whether FP-DMN connectivity in healthy children varied with age and intelligence quotient (IQ).

Methods: We utilized network-based statistics (NBS) to examine resting state functional connectivity between FP and DMN seeds in N = 133 7-25-year-olds (M = 15.80). Linear regression evaluated FP-DMN associations with IQ.

Results: We detected NBS subnetworks containing both within- and between-network connections that were inversely associated with age. Four FP-DMN connections showed more negative connectivity between FP (inferior frontal gyrus and precentral gyrus) and DMN regions (frontal medial cortex, precuneus, and frontal pole) among older participants. Frontal pole-precentral gyrus connectivity inversely associated with IQ.

Conclusions: FP-DMN connectivity was more anticorrelated at older ages, potentially indicating dynamic network segregation of these circuits from childhood to early adulthood. Youth with more mature (i.e., anticorrelated) FP-DMN connectivity demonstrated higher IQ. Our findings add to the growing body of literature examining neural network development and its association with IQ.
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http://dx.doi.org/10.1016/j.dcn.2021.100928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848769PMC
April 2021

Depression Risk Is Associated With Weakened Synchrony Between the Amygdala and Experienced Emotion.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 03 2;6(3):343-351. Epub 2020 Nov 2.

Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York; Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York. Electronic address:

Background: Major depressive disorder (MDD) is associated with aberrant limbic neural responses to emotional stimuli. We assessed how self-generated emotions modulate trial-by-trial limbic activity and whether this brain-emotion synchrony varies by familial MDD risk (regardless of personal MDD history) and neuroticism.

Methods: Participants (n = 74, mean age = 34 years) were later-generation family members of depressed or nondepressed probands as part of a longitudinal cohort study. Using an emotion induction task, we examined participant-specific modulation of anatomically defined limbic neurobiology. Neuroticism, mental health, and familial parenting style were assessed, and MDD assessments were routinely collected throughout the previous longitudinal assessments of the study.

Results: Participant-specific emotional arousal modulated amygdala and hippocampal activity. Lasso regression identified attenuated right amygdala arousal modulation as being relatively more associated with neuroticism (even though neuroticism was not associated with arousal ratings). Attenuated amygdala modulation and neuroticism were significantly more likely in offspring of parents with MDD. Parental MDD, but not personal history of MDD, predicted attenuated amygdala modulation.

Conclusions: Attenuated right amygdala modulation by emotional arousal was associated with neuroticism, indicating that the amygdala was less synchronous with emotional experiences in individuals higher in neuroticism. This neurophenotype was predicted by participants' parental MDD history but not by their own MDD history; that is, it was observed in unaffected and affected offspring of parents with MDD. These data suggest that weak amygdala-emotion synchrony may be a predisposing risk factor for MDD, rather than a result of the illness, and they suggest pathways by which this risk factor for depression is passed intergenerationally.
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http://dx.doi.org/10.1016/j.bpsc.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946704PMC
March 2021

Nucleic acid sample preparation from whole blood in a paper microfluidic device using isotachophoresis.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 13;1163:122494. Epub 2020 Dec 13.

Department of Mechanical Engineering, University of Washington, Seattle, WA, USA; Department of Chemical Engineering, University of Washington, Seattle, WA, USA; Department of Family Medicine, University of Washington, Seattle, WA, USA. Electronic address:

Nucleic acid amplification tests (NAATs) are a crucial diagnostic and monitoring tool for infectious diseases. A key procedural step for NAATs is sample preparation: separating and purifying target nucleic acids from crude biological samples prior to nucleic acid amplification and detection. Traditionally, sample preparation has been performed with liquid- or solid-phase extraction, both of which require multiple trained user steps and significant laboratory equipment. The challenges associated with sample preparation have limited the dissemination of NAAT point-of-care diagnostics in low resource environments, including low- and middle-income countries. We report on a paper-based device for purification of nucleic acids from whole blood using isotachophoresis (ITP) for point-of-care NAATs. We show successful extraction and purification of target nucleic acids from large volumes (33 µL) of whole human blood samples with no moving parts and few user steps. Our device utilizes paper-based buffer reservoirs to fully contain the liquid ITP buffers and does not require complex filling procedures, instead relying on the natural wicking of integrated paper membranes. We perform on-device blood fractionation via filtration to remove leukocytes and erythrocytes from our sample, followed by integrated on-paper proteolytic digestion of endogenous plasma proteins to allow for successful isotachophoretic extraction. Paper-based isotachophoresis purifies and concentrates target nucleic acids that are added directly to recombinase polymerase amplification (RPA) reactions. We show consistent amplification of input copy concentrations of as low as 3 × 10 copies nucleic acid per mL input blood with extraction and purification taking only 30 min. By employing a paper architecture, we are able to incorporate these processes in a single, robust, low-cost design, enabling the direct processing of large volumes of blood, with the only intermediate user steps being the removal and addition of tape. Our device represents a step towards a simple, fully integrated sample preparation system for nucleic acid amplification tests at the point-of-care.
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http://dx.doi.org/10.1016/j.jchromb.2020.122494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115986PMC
January 2021

Genetic Studies of Mental Illness: Are Children Being Left Behind?

J Am Acad Child Adolesc Psychiatry 2021 Jun 29;60(6):672-674. Epub 2020 Dec 29.

Columbia University Vagelos College of Physicians and Surgeons, New York; New York State Psychiatric Institute, New York; Center for Intergenerational Psychiatry at the New York State Psychiatric Institute.

Understanding the genetic architecture of psychiatric disorders is paramount to linking psychopathologies to their genetic underpinnings. In turn, this knowledge can inform strategies for identifying high-risk individuals, early intervention, and development of personalized treatment approaches. Over the past 2 decades, owing to lowering per capita costs and relative ease of analysis, a plethora of studies have used single nucleotide polymorphism genotyping and genome-wide association studies (GWASs) to unravel common and rare risk loci underlying psychiatric disorders and their endophenotypes. In contrast to the single allele focus of classical Mendelian inheritance, mental illnesses are often polygenic in nature with multiple common genetic variants, each contributing a small, but meaningful added risk. By interrogating the entire genome, GWASs have allowed the functional assessment of promising candidate genes in in vivo as well as in vitro models of psychiatric disease. Further, these findings have spawned the approach of calculating polygenic risk scores, a promising strategy for inferring genetic susceptibility to the development of psychopathology by taking into account the polygenic structure of psychiatric disorders.
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http://dx.doi.org/10.1016/j.jaac.2020.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184577PMC
June 2021

ADHD and risk for subsequent adverse childhood experiences: understanding the cycle of adversity.

J Child Psychol Psychiatry 2020 Dec 2. Epub 2020 Dec 2.

New York State Psychiatric Institute, Columbia University Irving Medical Center, New York, NY, USA.

Background: Children with adverse childhood experiences (ACEs) are more likely to develop Attention-Deficit/Hyperactivity Disorder (ADHD). The reverse relationship - ADHD predicting subsequent ACEs - is vastly understudied, although it may be of great relevance to underserved populations highly exposed to ACEs.

Methods: Participants were 5- to 15-year-olds (48% females) with (9.9%) and without ADHD (DSM-IV criteria except age of onset) in a longitudinal population-based study of Puerto Rican youth. In each wave (3 yearly assessments, W1-3), ten ACEs (covering parental loss and maladjustment and child maltreatment) were examined, plus exposure to violence. Logistic regression models examined ADHD (including subtypes) and subsequent risk for ACEs. Also considered were interactions by age, sex, number of W1 ACEs, and recruitment site.

Results: Children with W1 ADHD were more likely to experience subsequent adversity (OR: 1.63; 95% CI: 1.12-2.37) accounting for child age, sex, public assistance, maternal education, site, disruptive behavior disorders, and W1 ACEs. Inattentive (OR: 2.00; 95% CI: 1.09-3.66), but not hyperactive/impulsive or combined ADHD, predicted future ACEs.

Conclusions: ADHD predicts subsequent risk for ACEs, and the inattentive presentation may confer the most risk. Inattentive presentations could pose a bigger risk given differences in symptom persistence, latency to access to treatment, and treatment duration. The present study suggests a pathway for the perpetuation of adversity, where bidirectional relationships between ADHD and ACEs may ensnare children in developmental pathways predictive of poor outcomes. Understanding the mechanism underlying this association can help the development of interventions that interrupt the cycle of adversity exposure and improve the lives of children with ADHD.
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http://dx.doi.org/10.1111/jcpp.13352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169708PMC
December 2020

Concordance in parent and offspring cortico-basal ganglia white matter connectivity varies by parental history of major depressive disorder and early parental care.

Soc Cogn Affect Neurosci 2020 10;15(8):889-903

Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Social behavior is transmitted cross-generationally through coordinated behavior within attachment bonds. Parental depression and poor parental care are major risks for disruptions of such coordination and are associated with offspring's psychopathology and interpersonal dysfunction. Given the key role of the cortico-basal ganglia (CBG) circuits in social communication, we examined similarities (concordance) of parent-offspring CBG white matter (WM) connections and how parental history of major depressive disorder (MDD) and early parental care moderate these similarities. We imaged 44 parent-offspring dyads and investigated WM connections between basal-ganglia seeds and selected regions in temporal cortex using diffusion tensor imaging (DTI) tractography. We found significant concordance in parent-offspring strength of CBG WM connections, moderated by parental lifetime-MDD and care. The results showed diminished neural concordance among dyads with a depressed parent and that better parental care predicted greater concordance, which also provided a protective buffer against attenuated concordance among dyads with a depressed parent. Our findings provide the first neurobiological evidence of concordance between parents-offspring in WM tracts and that concordance is diminished in families where parents have lifetime-MDD. This disruption may be a risk factor for intergenerational transmission of psychopathology. Findings emphasize the long-term role of early caregiving in shaping the neural concordance among at-risk and affected dyads.
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http://dx.doi.org/10.1093/scan/nsaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543940PMC
October 2020

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity.

JAMA Pediatr 2020 Nov;174(11):1073-1081

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York.

Importance: Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight.

Objective: To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity.

Design, Setting, And Participants: This prospective birth cohort study from the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020.

Exposures: Acetaminophen levels measured in meconium.

Main Outcomes And Measures: Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity.

Results: Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%).

Conclusions And Relevance: Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.
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http://dx.doi.org/10.1001/jamapediatrics.2020.3080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522774PMC
November 2020

Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.

Cereb Cortex Commun 2020 23;1(1):tgaa033. Epub 2020 Jul 23.

New York State Psychiatric Institute and Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Although severe early life stress has been shown to accelerate the development of frontolimbic resting-state functional connectivity (RSFC), less is known about the effects of socioeconomic disadvantage, a prolonged and multifaceted stressor. In a cross-sectional study of 127 participants aged 5-25, we examined whether lower neighborhood socioeconomic status (SES; measured by Area Deprivation Index and neighborhood poverty and educational attainment) was associated with prematurely reduced amygdala-ventromedial prefrontal cortex (vmPFC) RSFC. We further tested whether neighborhood SES was more predictive than household SES and whether SES effects on connectivity were associated with anxiety symptoms. We found reduced basolateral amygdala-vmPFC RSFC at earlier ages in participants from more disadvantaged neighborhoods; this effect was unique to neighborhood SES and absent for household SES. Furthermore, this reduced connectivity in more disadvantaged youth and increased connectivity in more advantaged youth were associated with less anxiety; children who deviated from the connectivity pattern associated with their neighborhood SES had more anxiety. These results demonstrate that neighborhood socioeconomic disadvantage is associated with accelerated maturation of amygdala-vmPFC RSFC and suggest that the pathophysiology of pediatric anxiety depends on a child's neighborhood socioeconomic characteristics. Our findings also underscore the importance of examining SES effects in studies of brain development.
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http://dx.doi.org/10.1093/texcom/tgaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503474PMC
July 2020

Differences in brain structure and function in children with the obesity-risk allele.

Obes Sci Pract 2020 Aug 1;6(4):409-424. Epub 2020 Apr 1.

Department of Psychiatry Columbia University Irving Medical Center New York New York USA.

Objective: Noncoding alleles of the fat mass and obesity-associated () gene have been associated with obesity risk, yet the underlying mechanisms remain unknown. Risk allele carriers show alterations in brain structure and function, but previous studies have not disassociated the effects of genotype from those of body mass index (BMI).

Methods: Differences in brain structure and function were examined in children without obesity grouped by their number of copies (0,1,2) of the FTO obesity-risk single-nucleotide polymorphism (SNP) rs1421085. One hundred five 5- to 10-year-olds (5th-95th percentile body fat) were eligible to participate. Usable scans were obtained from 93 participants (15 CC [homozygous risk], 31 CT [heterozygous] and 47 TT [homozygous low risk]).

Results: Homozygous C allele carriers (CCs) showed greater grey matter volume in the cerebellum and temporal fusiform gyrus. CCs also demonstrated increased bilateral cerebellar white matter fibre density and increased resting-state functional connectivity between the bilateral cerebellum and regions in the frontotemporal cortices.

Conclusions: This is the first study to examine brain structure and function related to alleles in young children not yet manifesting obesity. This study lends support to the notion that the cerebellum may be involved in -related risk for obesity, yet replication and further longitudinal study are required.
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http://dx.doi.org/10.1002/osp4.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448161PMC
August 2020

Altered Dentate Gyrus Microstructure in Individuals at High Familial Risk for Depression Predicts Future Symptoms.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 01 21;6(1):50-58. Epub 2020 Jun 21.

Department of Psychiatry, College of Physicians and Surgeons, New York, New York; Division of Translational Epidemiology, New York State Psychiatric Institute, New York, New York. Electronic address:

Background: Offspring of individuals with major depressive disorder (MDD) are at increased risk for developing MDD themselves. Altered hippocampal, and specifically dentate gyrus (DG), structure and function may be involved in depression development. However, hippocampal abnormalities could also be a consequence of the disease. For the first time, we tested whether abnormal DG micro- and macrostructure were present in offspring of individuals with MDD and whether these abnormalities predicted future symptomatology.

Methods: We measured the mean diffusivity of gray matter, a measure of microstructure, via diffusion tensor imaging and volume of the DG via structural magnetic resonance imaging in 102 generation 2 and generation 3 offspring at high and low risk for depression, defined by the presence or absence, respectively, of moderate to severe MDD in generation 1. Prior, current, and future depressive symptoms were tested for association with hippocampal structure.

Results: DG mean diffusivity was higher in individuals at high risk for depression, regardless of a lifetime history of MDD. While DG mean diffusivity was not associated with past or current depressive symptoms, higher mean diffusivity predicted higher symptom scores 8 years later. DG microstructure partially mediated the association between risk and future symptoms. DG volume was smaller in high-risk generation 2 but not in high-risk generation 3.

Conclusions: Together, these findings suggest that the DG has a role in the development of depression. Furthermore, DG microstructure, more than macrostructure, is a sensitive risk marker for depression and partially mediates future depressive symptoms.
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http://dx.doi.org/10.1016/j.bpsc.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750261PMC
January 2021

Family Environment, Neurodevelopmental Risk, and the Environmental Influences on Child Health Outcomes (ECHO) Initiative: Looking Back and Moving Forward.

Front Psychiatry 2020 19;11:547. Epub 2020 Jun 19.

Division of Child and Adolescent Psychiatry, Columbia University, New York, NY, United States.

The family environment, with all its complexity and diverse components, plays a critical role in shaping neurodevelopmental outcomes in children. Herein we review several domains of the family environment (family socioeconomic status, family composition and home environment, parenting behaviors and interaction styles, parental mental health and functioning, and parental substance use) and discuss how these domains influence neurodevelopment, with particular emphasis on mental health outcomes. We also highlight a new initiative launched by the National Institutes of Health, the Environmental influences on Child Health Outcomes (ECHO) program. We discuss the role that ECHO will play in advancing our understanding of the impact of the family environment on children's risk for psychiatric outcomes. Lastly, we conclude with important unanswered questions and controversies in this area of research, highlighting how ECHO will contribute to resolving these gaps in our understanding, clarifying relationships between the family environment and children's mental health.
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http://dx.doi.org/10.3389/fpsyt.2020.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318113PMC
June 2020

Excitation-Emission Matrix Spectroscopy for Analysis of Chemical Composition of Combustion Generated Particulate Matter.

Environ Sci Technol 2020 07 12;54(13):8198-8209. Epub 2020 Jun 12.

University of Washington, Mechanical Engineering, Seattle, Washington 98195, United States.

Analysis of particulate matter (PM) is important for the assessment of human exposures to potentially harmful agents, notably combustion-generated PM. Specifically, polycyclic aromatic hydrocarbons (PAHs) found in ultrafine PM have been linked to cardiovascular diseases and carcinogenic and mutagenic effects. In this study, we quantify the presence and concentrations of PAHs with lower molecular weight (LMW, 126 < MW < 202) and higher molecular weight (HMW, 226 < MW < 302), i.e., smaller and larger than Pyrene, in combustion-generated PM using excitation-emission matrix (EEM) fluorescence spectroscopy. Laboratory combustion PM samples were generated in a laminar diffusion inverted gravity flame reactor (IGFR) operated on ethylene and ethane. Fuel dilution by Ar in 0% to 90% range controlled the flame temperature. The colder flames result in lower PM yields however, the PM PAH content increases significantly. Temperature thresholds for PM transition from low to high organic carbon content were characterized based on the maximum flame temperature ( ∼ 1791 to 1857 K) and the highest soot luminosity region temperature ( ∼ 1600 to 1650K). Principal component regression (PCR) analysis of the EEM spectra of IGFR samples correlates to GCMS data with R = 0.988 for LMW and 0.998 for HMW PAHs. PCR-EEM analysis trained on the IGFR samples was applied to PM samples from woodsmoke and diesel exhaust, the model accurately predicts HMW PAH concentrations with R = 0.976 and overestimates LMW PAHs.
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http://dx.doi.org/10.1021/acs.est.0c01110DOI Listing
July 2020

Enzymatic and Chemical-Based Methods to Inactivate Endogenous Blood Ribonucleases for Nucleic Acid Diagnostics.

J Mol Diagn 2020 08 22;22(8):1030-1040. Epub 2020 May 22.

Department of Mechanical Engineering, University of Washington, Seattle, Washington; Department of Chemical Engineering, University of Washington, Seattle, Washington; Department of Family Medicine, University of Washington, Seattle, Washington. Electronic address:

There are ongoing research efforts into simple and low-cost point-of-care nucleic acid amplification tests (NATs) addressing widespread diagnostic needs in resource-limited clinical settings. Nucleic acid testing for RNA targets in blood specimens typically requires sample preparation that inactivates robust blood ribonucleases (RNases) that can rapidly degrade exogenous RNA. Most NATs rely on decades-old methods that lyse pathogens and inactivate RNases with high concentrations of guanidinium salts. Herein, we investigate alternatives to standard guanidinium-based methods for RNase inactivation using an activity assay with an RNA substrate that fluoresces when cleaved. The effects of proteinase K, nonionic surfactants, SDS, dithiothreitol, and other additives on RNase activity in human serum are reported. Although proteinase K has been widely used in protocols for nuclease inactivation, it was found that high concentrations of proteinase K are unable to eliminate RNase activity in serum, unless used in concert with denaturing concentrations of SDS. It was observed that SDS must be combined with proteinase K, dithiothreitol, or both for irreversible and complete RNase inactivation in serum. This work provides an alternative chemistry for inactivating endogenous RNases for use in simple, low-cost point-of-care NATs for blood-borne pathogens.
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http://dx.doi.org/10.1016/j.jmoldx.2020.04.211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416074PMC
August 2020

Intergenerational psychiatry: a new look at a powerful perspective.

World Psychiatry 2020 Jun;19(2):175-176

Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University Medical Center - New York State Psychiatric Institute, New York, NY, USA.

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http://dx.doi.org/10.1002/wps.20733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214952PMC
June 2020

Excitation Emission Matrix Fluorescence Spectroscopy for Combustion Generated Particulate Matter Source Identification.

Atmos Environ (1994) 2020 Jan 22;220. Epub 2019 Oct 22.

Department of Chemical Engineering, Critical Care and Sleep Medicine University of Washington.

The inhalation of particulate matter (PM) is a significant health risk associated with reduced life expectancy due to increased cardio-pulmonary disease and exacerbation of respiratory diseases such as asthma and pneumonia. PM originates from natural and anthropogenic sources including combustion engines, cigarettes, agricultural burning, and forest fires. Identifying the source of PM can inform effective mitigation strategies and policies, but this is difficult to do using current techniques. Here we present a method for identifying PM source using excitation emission matrix (EEM) fluorescence spectroscopy and a machine learning algorithm. We collected combustion generated PM from wood burning, diesel exhaust, and cigarettes using filters. Filters were weighted to determine mass concentration followed by extraction into cyclohexane and analysis by EEM fluorescence spectroscopy. Spectra obtained from each source served as training data for a convolutional neural network (CNN) used for source identification in mixed samples. This method can predict the presence or absence of the three laboratory sources with an overall accuracy of 89% when the threshold for classifying a source as present is 1.1 μg/m in air over a 24-hour sampling time. The limit of detection for cigarette, diesel and wood are 0.7, 2.6, 0.9 μg/m, respectively, in air assuming a 24-hour sampling time at an air sampling rate of 1.8 liters per minute. We applied the CNN algorithm developed using the laboratory training data to a small set of field samples and found the algorithm was effective in some cases but would require a training data set containing more samples to be more broadly applicable.
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http://dx.doi.org/10.1016/j.atmosenv.2019.117065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111209PMC
January 2020

Enzymatic Assay for Rapid Measurement of Antiretroviral Drug Levels.

ACS Sens 2020 04 15;5(4):952-959. Epub 2020 Apr 15.

Department of Mechanical Engineering, University of Washington, Seattle, Washington 98195, United States.

Poor adherence to pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) can lead to human immunodeficiency virus (HIV) acquisition and emergence of drug-resistant infections, respectively. Measurement of antiviral drug levels provides objective adherence information that may help prevent adverse health outcomes. Gold-standard drug-level measurement by liquid chromatography/mass spectrometry is centralized, heavily instrumented, and expensive and is thus unsuitable and unavailable for routine use in clinical settings. We developed the REverSe TRanscrIptase Chain Termination (RESTRICT) assay as a rapid and accessible measurement of drug levels indicative of long-term adherence to PrEP and ART. The assay uses designer single-stranded DNA templates and intercalating fluorescent dyes to measure complementary DNA (cDNA) formation by reverse transcriptase in the presence of nucleotide reverse transcriptase inhibitor drugs. We optimized the RESTRICT assay using aqueous solutions of tenofovir diphosphate (TFV-DP), a metabolite that indicates long-term adherence to ART and PrEP, at concentrations over 2 orders of magnitude above and below the clinically relevant range. We used dilution in water as a simple sample preparation strategy to detect TFV-DP spiked into whole blood and accurately distinguished TFV-DP drug levels corresponding to low and high PrEP adherences. The RESTRICT assay is a fast and accessible test that could be useful for patients and clinicians to measure and improve ART and PrEP adherence.
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http://dx.doi.org/10.1021/acssensors.9b02198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183420PMC
April 2020

Attention-deficit hyperactivity disorder.

Lancet 2020 02 23;395(10222):450-462. Epub 2020 Jan 23.

Department of Child and Adolescent Psychiatry, King's College London, London, UK.

Attention-deficit hyperactivity disorder (ADHD), like other psychiatric disorders, represents an evolving construct that has been refined and developed over the past several decades in response to research into its clinical nature and structure. The clinical presentation and course of the disorder have been extensively characterised. Efficacious medication-based treatments are available and widely used, often alongside complementary psychosocial approaches. However, their effectiveness has been questioned because they might not address the broader clinical needs of many individuals with ADHD, especially over the longer term. Non-pharmacological approaches to treatment have proven less effective than previously thought, whereas scientific and clinical studies are starting to fundamentally challenge current conceptions of the causes of ADHD in ways that might have the potential to alter clinical approaches in the future. In view of this, we first provide an account of the diagnosis, epidemiology, and treatment of ADHD from the perspective of both the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and the eleventh edition of the International Classification of Diseases. Second, we review the progress in our understanding of the causes and pathophysiology of ADHD on the basis of science over the past decade or so. Finally, using these discoveries, we explore some of the key challenges to both the current models and the treatment of ADHD, and the ways in which these findings can promote new perspectives.
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http://dx.doi.org/10.1016/S0140-6736(19)33004-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880081PMC
February 2020

Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities.

Pediatrics 2019 09;144(3)

Brown Center for the Study of Children at Risk and Departments of Psychiatry and Human Behavior and Pediatrics, Alpert Medical School, Brown University, Providence, Rhode Island.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.
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http://dx.doi.org/10.1542/peds.2019-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759228PMC
September 2019

The association between antidepressant treatment and brain connectivity in two double-blind, placebo-controlled clinical trials: a treatment mechanism study.

Lancet Psychiatry 2019 08 24;6(8):667-674. Epub 2019 Jun 24.

New York State Psychiatric Institute, Columbia University, New York, NY, USA; Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

Background: Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies.

Methods: We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised).

Findings: Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: β=-0·06; 95% CI -0·08 to -0·03; p<0·0001, η=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, η=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299).

Interpretation: The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics.

Funding: National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.
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http://dx.doi.org/10.1016/S2215-0366(19)30179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937159PMC
August 2019