Target Treatment Research Articles

Biomarkers of macrophage-associated inflammatory pathways are associated with OA symptoms and radiographic disease

Purpose: Although the role of inflammation in osteoarthritis has been heavily debated, recent evidence has demonstrated macrophage involvement in knee osteoarthritis (OA). Using etarfolatide (EC20) nuclear imaging that detects folate receptors, we have observed activated macrophages in human knee OA joints whose quantity are correlated with both radiographic and symptom severity of knee OA. In addition, we identified synovial fluid (SF) biomarkers, CD163 and CD14, that function as quantitative traits of the etarfolatide-positive phenotype and that predict knee OA progression over 3 years, allowing for the identification of inflammatory OA phenotypes. The purpose of this study was to characterize a molecular biological profile for identifying subsets of subjects with an inflammatory OA phenotype through the investigation of the association of an extensive array of synovial fluid biomarkers with the severity of macrophage infiltration, radiographic knee OA and pain. Methods: The Institutional Review Board approved all procedures and the study was registered at ClinicalTrials.gov (NCT01237405). Participants (n = 25) with radiographic knee OA in at least one knee and knee pain underwent bilateral knee etarfolatide imaging. SF was obtained by either direct aspiration (n = 28 knees) or by lavage (n = 20 knees) when direct aspiration was not possible. Samples were stored at -80 until analyzed. The intensity of etarfolatide imaging of the knee and pain assessment by NHANES criteria were scored semi-quantitatively as normal (score 0), mild (score 1), moderate (score 2), or severe (score 3). Radiographs were scored for Kellgren Lawrence (KL) grade (0-4), joint space narrowing (JSN, 0-3) and osteophyte (OST, 0-3). Biomarkers were quantified by Rules Based Medicine (RBM) using the high sensitivity multiplex immunoassay, Myriad Human InflammationMAP 1.0, including 47 different cytokines, chemokines, and growth factors related to inflammation. Biomarker concentrations in lavage fluid were corrected for dilution by an established urea method. Multivariable linear regression models using generalized estimating equations (GEEs) were performed to evaluate associations of biomarker concentrations with etarfolatide scores, radiographic OA severity, and OA symptoms, adjusting for age, gender and BMI. False discovery rate (FDR) was controlled using the Benjamini-Hochberg method. Spearman correlations were used to test for associations of informative RBM markers with sfCD163 and sfCD14. Results: Participants were 72% female, mean age of 62.4 (range 30-89) and a mean BMI of 29.2 (range 22.5-38.4 kg/m2). The majority (76%) of participants had moderate to severe bilateral radiographic knee OA with 24% having a KL grade 1, 58% KL grade 2-3, and 18% KL grade 4. Significant associations of SF biomarkers included sVCAM-1 and MMP-3 with the presence of activated macrophages (etarfolatide scan), sVCAM-1, sICAM-1, TIMP-1, and VEGF with radiographic OA severity (KL, JSN, and OST), and VEGF, MMP-3, TIMP-1, sICAM-1, sVCAM-1, and MCP-1 with OA symptoms (Table 1). These SF biomarkers were all highly correlated with sfCD163 and sfCD14. Conclusions: This study provides evidence in support of an inflammatory OA subphenotype characterized by the presence of activated macrophages and its association with synovial fluid biomarkers of inflammation and angiogenesis. These processes may interrelate as VEGF, a biomarker of angiogenesis, can increase expression of MMPs and inflammation, and markers of vascular adhesion, VCAM-1 and ICAM-1 correlate with synovitis. This biomarker profile may assist in identifying patients with an inflammatory OA phenotype for targeting of treatment to modulate inflammation and activated macrophages.

T2 , T1ρ and TRAFF4 detect early regenerative changes in mouse ischemic skeletal muscle.

The identification of areas with regenerative potential in ischemic tissues would allow the targeting of treatments supporting tissue recovery. The regeneration process involves the activation of several cellular and molecular responses which could be detected using magnetic resonance imaging (MRI). However, to date, magnetic resonance (MR) relaxation parameters have received little attention in the diagnosis and follow-up of limb ischemia. The purpose of this study was to evaluate the feasibility of different MRI relaxation and diffusion tensor imaging parameters in the detection of areas showing early signs of regeneration in ischemic mouse skeletal muscles. T2 and T1ρ relaxation time constants, together with TRAFFn , T1 and diffusion tensor imaging, were evaluated to differentiate areas of regeneration in a mouse hind limb ischemia model before and 0, 1, 4, 7, 14 and 30days after ischemia. All the measured relaxation times were longer in the areas of early regeneration compared with normal muscle tissue. The relaxation times increased after ischemia in the ischemic muscles, reaching a maximum at 4-7days after occlusion, coinciding with the appearance of early signs of regeneration. Fractional anisotropy decreased significantly (p < 0.05) on days 1-4, whereas mean diffusivity, λ1 and λ2 decreased later, starting at day 7 after ischemia compared with the pre-operational time point. The percentages of areas with different tissue morphologies were determined based on histological analysis of the ischemic muscle cross-sections, and correlations between the percentages obtained and different relaxation times were calculated. The highest correlation between relaxation times and histology was achieved with T2 , T1ρ and TRAFF4 (R2 = 0.96, R2 = 0.92 and R2 = 0.84, respectively, p < 0.01). Early regenerative changes were visible using T2 , T1ρ and TRAFF4 MR relaxation time constants in skeletal muscle after ischemia. These markers could potentially be used for the identification of targets for therapies supporting muscle regeneration after ischemic injury.

Clinical course and prognostic factors across different musculoskeletal pain sites: A secondary analysis of individual patient data from randomised clinical trials.

Previous research has identified similar prognostic factors in patients with musculoskeletal (MSK) conditions regardless of pain presentation, generating opportunities for management based on prognosis rather than specific pain presentation. Data from seven RCTs (2483 participants) evaluating a range of primary care interventions for different MSK pain conditions were used to investigate the course of symptoms and explore similarities and differences in predictors of outcome. The value of pain site for predicting changes in pain and function was investigated and compared with that of age, gender, social class, pain duration, widespread pain and level of anxiety/depression. Over the initial three months of follow-up, changes in mean pain intensity reflected an improvement, with little change occurring after this period. Participants with knee pain due to osteoarthritis (OA) showed poorer long-term outcome (mean difference in pain reduction at 12months -1.85, 95% CI -2.12 to -1.57, compared to low back pain). Increasing age, manual work, longer pain duration, widespread pain and increasing anxiety/depression scores were significantly associated with poorer outcome regardless of pain site. Testing of interactions showed some variation between pain sites, particularly for knee OA, where age, manual work and pain duration were most strongly associated with outcome. Despite some differences in prognostic factors for trial participants with knee OA who were older and had more chronic conditions, similarity of outcome predictors across regional MSK pain sites provides evidence to support targeting of treatment based on prognostic factors rather than site of pain. Individual patient data analysis of trials across different regional musculoskeletal pain sites was used to evaluate course and prognostic factors associated with pain and disability. Overall, similarity of outcome predictors across these different pain sites supports targeting of treatment based on prognostic factors rather than pain site alone.

Better Together? Social Networks in Truancy and the Targeting of Treatment

Truancy correlates with many risky behaviors and adverse outcomes. We use detailed administrative data on by-class absences to construct social networks based on students who miss class together. We simulate these networks and use permutation tests to show that certain students systematically coordinate their absences. Leveraging a parent-information intervention on student absences, we find spillover effects from treated students onto peers in their network. We show that an optimal-targeting algorithm that incorporates machine-learning techniques to identify heterogeneous effects, as well as the direct effects and spillover effects, could further improve the efficacy and cost-effectiveness of the intervention subject to a budget constraint.

Better Together? Social Networks in Truancy and the Targeting of Treatment

Truancy correlates with many risky behaviors and adverse outcomes. We use detailed administrative data on by-class absences to construct social networks based on students who miss class together. We simulate these networks and use permutation tests to show that certain students systematically coordinate their absences. Leveraging a parent-information intervention on student absences, we find spillover effects from treated students onto peers in their network. We show that an optimal-targeting algorithm that incorporates machine-learning techniques to identify heterogeneous effects, as well as the direct effects and spillover effects, could further improve the efficacy and cost-effectiveness of the intervention subject to a budget constraint.

Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)–octadecylamine conjugate for lung cancer treatment

Poly(sialic acid) (PSA) is a natural hydrophilic biodegradable and non-immunogenic biopolymer, receptors for its monomer are expressed on peripheral blood neutrophils (PBNs), which plays important roles in the progression and invasion of tumors. A poly(sialic acid)–octadecylamine conjugate (PSA–ODA) was synthesized and then anchor it on the surface of liposomal pixantrone (Pix-PSL), to achieve an improved anticancer effect. The liposomes were prepared using a remote loading method via a pH gradient, and then assessed for particle size, zeta potential encapsulation efficiency, in vitro release, and in vitro cytotoxicity. Simultaneously, in vitro and in vivo cellular uptake studies confirmed that PSA-decorated liposomes provided an enhanced accumulation of liposomes in PBNs. An in vivo study presented that the anti-tumor activity of Pix-PSL was superior to that of other Pix formulations, probably due to the efficient targeting of PBNs by Pix-PSL, after which PBN containing Pix-PSL (Pix-PSL/PBNs) in the blood circulation are recruited by the tumor microenvironment. These findings suggest that PSA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumors, which represents a promising approach for the tumor targeting of chemotherapeutic treatments.

Commentary on "Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force".

Objectives To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. Methods The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. Results Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. Conclusions This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

The History of Ultrasound and Its Use at Point of Care: Neonatal Ultrasound in Transport

Purpose of review The purposes of this review are to explore the history of the diagnostic ultrasound and its use in medical care and to report on the latest findings on the utility of ultrasound during the transport of patients. Recent findings The Neonatal Ultrasound in Transport (NUiT) study demonstrated the feasibility and utility of ultrasound assessment prior to the retrieval of critically ill newborns to a higher level of care. It is feasible to carry a laptop ultrasound with the transport team without hindering flight or retrieval processes. The NUiT study demonstrated that many term babies had evidence of clinically unsuspected haemodynamic compromise. Other babies had clinically unsuspected abnormal heart structure allowing for redirection of transport toward paediatric cardiology centres. The preterm cohort revealed many babies with clinically unsuspected low systemic blood flow and stable head ultrasound findings pre- and post transport. This has implications for therapeutic targeting of treatment and for counselling parents. Summary Clinician-performed ultrasound (CPU) during the retrieval of neonates confirms a high incidence of haemodynamic pathology. Ultrasound in retrieval is feasible, allows the accurate triage of babies to cardiac centres and may allow more accurate and earlier targeting of fluid and inotropic support.

Sleep disorders have an influence on immune function and the development of sepsis

Background Neuro-immune-endocrine system plays an important role in the pathological process of sepsis, sleep disorders intervenes significantly the function of neuro-immune system. We pay more attention to some studies of sepsis about that different types of sleep disorders can lead to immune dysfunction. Objective This review elucidates that diverse sleep disorders have influence on immune system regulation and the development of sepsis. This review also summarizes new control strategies for the neural-immune-endocrine treatment of sepsis. Content We summarize sleep disorder types, animal and clinical studies about influences of sleep disorders on immune function and the development of sepsis. Trend Sleep disorders are widespread social problems that influence human health seriously. It causes neuro-immune-endocrine dysfunction which leads to poor prognosis of sepsis. Thus, regulation of neuro-immune-endocrine system will open the new targeting of sepsis treatment. Key words: Sleep disorders; Immunity; Neuroimmunomodulation; Sepsis

A comparison of two different anthelmintic treatment regimens against natural gastrointestinal nematode infections on two Lithuanian sheep farms

BackgroundAccording to targeted treatment (TT), the whole flock is dewormed based on knowledge of the risk, or parameters that quantify the mean level of infection, whereas according to targeted selective treatment (TST), only individual animals within the grazing group are treated, based on parasitological, production and/or morbidity parameters. The aim of this study was to compare two different treatment protocols on sheep farms in Lithuania. The study was conducted from 15 April to 31 October 2014 on three sheep farms. On the TT (the whole flock) and T(S)T (with FECs ≥ 300, respectively) farms all adult animals were treated orally with fenbendazole irrespective of EPG counts before the grazing season. The second treatment was applied with injectable ivermectin on both farms. However, on the TT farm all sheep were also treated on 2nd August regardless of their EPG counts, while on the T(S)T farm only those animals with an EPG ≥ 300 were treated on 1 July using a threshold of ≥ 300 EPG. No treatments were administered on the control farm (n = 1) during the study.ResultsSpring treatment of ewes significantly reduced nematode faecal egg counts (FEC) both on the TT and T(S)T farms, with the benefit of lowering pasture contamination with infective L3 stage larvae at the start of grazing season, while it remained significantly higher on the control farm. The positive effect of the spring treatment of ewes was reflected by increased body weight gains (BWG) in lambs in the first half of the grazing season. Following the second treatment, the weight gains in lambs on the T(S)T farm were higher compared to lambs on the TT farm, while BWG in the control lambs started to decrease. The difference was also substantiated by the body condition scores (BCS) and dag scores (DS) of lambs, which were highest on the T(S)T farm compared with those on the control and TT farms.ConclusionsThe results of this study show that both treatment strategies were useful in reducing clinical effects (BCS and DS) of gastrointestinal nematode parasitism and increasing the performance in lambs. Furthermore, on the T(S)T farm some of animals were left in refugia, helping to slow down the development of anthelmintic resistance (AR) in future.

Novel strategies for the treatment of acute pancreatitis based on the determinants of severity

Acute pancreatitis (AP) is a common disease for which a specific treatment remains elusive. The key determinants of the outcome from AP are persistent organ failure and infected pancreatic necrosis. The prevention and treatment of these determinants provides a framework for the development of specific treatment strategies. The gut-lymph concept provides a common mechanism for systemic inflammation and organ dysfunction. Acute and critical illness, including AP, is associated with intestinal ischemia and drastic changes in the composition of gut lymph, which bypasses the liver to drain into the systemic circulation immediately proximal to the major organ systems which fail. The external diversion of gut lymph and the targeting of treatments to counter the toxic elements in gut lymph offers novel approaches to the prevention and treatment of persistent organ failure. Infected pancreatic necrosis is increasingly treated with less invasive techniques, the mainstay of which is drainage, both endoscopic and percutaneous. Further improvements will occur with the strategies to accelerate liquefaction and through a fundamental re-design of drains, both of which will increase drainage efficacy. The determinants of severity and outcome in patients admitted with AP provide the basis for innovative treatment strategies. The priorities are to translate the gut-lymph concept to clinical practice and to improve the design and active use of drains for infected complications of AP.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

ObjectivesTo aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus‐based guidance paper for the methodology and design of cognition trials in bipolar disorder.MethodsThe task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face‐to‐face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved.ResultsKey methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non‐study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach.ConclusionsThis ISBD task force guidance paper provides the first consensus‐based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples

Breast-to-brain metastasis (BBM) often represents a terminal event, due to the inability of many systemic treatments to cross the blood–brain barrier (BBB), rendering the brain a sanctuary site for tumour cells. Identifying genetic variations that can predict the patients who will develop BBM would allow targeting of adjuvant treatments to reduce risk while disease bulk is minimal. Germ-line genetic variations may contribute to whether a BBM forms by influencing the primary tumour subtype that presents, or by influencing the host response to the tumour or treatment regimen, or by facilitating transition of tumour cells across the BBB and establish a viable brain metastasis. The role of mitochondrial DNA (mtDNA) variants specifically in BBM is underexplored. Consequently, using a sensitive deep sequencing approach, we characterized the mtDNA variation landscapes of blood samples derived from 13 females who were diagnosed with early-onset breast cancer and later went on to develop BBM. We also predicted the potential pathogenic significance of variations identified in all mtDNA-encoded oxidative phosphorylation (OXPHOS) proteins using 3D protein structural mapping and analysis, to identify variations worthy of follow-up. From the 70 variations found in protein coding regions, we reveal novel links between three specific mtDNA variations and altered OXPHOS structure and function in 23% of the BBM samples. Further studies are required to confirm the origin of mtDNA variations, and whether they correlate with (1) the predicted alterations in mitochondrial function and (2) increased risk of developing breast-to-brain metastasis using a much larger cohort of samples.

Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects. Subjects with obese HFpEF (body mass index ≥35 kg/m2; n=99), nonobese HFpEF (body mass index <30 kg/m2; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing. Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563-4333 mL] versus 2772 mL [2555-3133 mL], and 2680 mL [2380-3006 mL]; P<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm, P=0.0005; length, 66±7 versus 61±7 and 61±7 mm, P<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm; P<0.0001), and greater total epicardial heart volume (945 mL [831-1105 mL] versus 797 mL [643-979 mL] and 632 mL [517-768 mL]; P<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both P<0.05) but not in nonobese HFpEF (P≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20; P=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12; P<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (P for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg; P<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve. Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.

Differentiated psychopharmacological treatment in three genetic subtypes of 22q11.2 deletion syndrome

IntroductionThe 22q11.2 deletion syndrome (22q11DS), mostly caused by the common deletion including the TBX- and COMT-genes (LCR22A-D), is highly associated with somatic anomalies. The distal deletion (distal of LCR22D) comprises the MAPK1-gene and is associated with specific heart defects. The rare central deletion (LCR22B-D) encompasses the CRKL-gene and shows predominantly urogenital anomalies. 22q11DS also differs in its neuropsychiatric profile: common deletion accompanied by schizophrenia-like psychoses and autism spectrum disorders, distal deletion by anxiety disorders, and central deletion by autistic-like behaviours.ObjectivesInvestigating genetic subtypes of 22q11DS.AimsAchieving a targeted pharmacological treatment based on genetic sub-typing.MethodsThirty-two patients with genetically proven 22q11DS, referred for detailed neuropsychiatric analysis.ResultsApart from two patients with distal deletion and one with central deletion, common 22q11.2 deletion was detected in 29 patients. Those with the common deletion were typified by a history of relapsing schizophrenia-like psychoses and partial non-response to conventional antipsychotics. In most patients, anxieties and mood instability were also manifest. The two patients with a distal deletion predominantly showed anxiety symptoms, while the behaviour of the patient with a central deletion was characterized by symptoms from the autism spectrum. Most patients with a common deletion could successfully be treated with clozapine or quetiapine, often combined with valproic acid. One patient with a distal deletion showed full remission upon treatment with citalopram (the second refused such a pharmacological intervention). The behaviour of the patient with central deletion improved upon contextual measures only.ConclusionsThe genetic subtype of 22q11DS enables targeting of treatment strategy.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Stratification of Latent Mycobacterium tuberculosis Infection by Cellular Immune Profiling.

Recently acquired and remotely acquired latent Mycobacterium tuberculosis infection (LTBI) are clinically indistinguishable, yet recent acquisition of infection is the greatest risk factor for progression to tuberculosis in immunocompetent individuals. We aimed to evaluate the ability of cellular immune signatures that differ between active tuberculosis and LTBI to distinguish recently from remotely acquired LTBI. Fifty-nine individuals were recruited: 20 had active tuberculosis, 19 had recently acquired LTBI, and 20 had remotely acquired LTBI. The proportion of mycobacteria-specific CD4+ T cells secreting tumor necrosis factor α (TNF-α) but not interferon γ or interleukin 2 which had a differentiated effector phenotype (TNF-α-only TEFF), and the level of CD27 expression on IFN-γ-producing CD4+ T cells, were detected by flow cytometry. The TNF-α-only TEFF signature was significantly higher in the group with recently acquired LTBI, compared with the group with remotely acquired LTBI (P < .0001), and it discriminated between these groups with high sensitivity and specificity, with an area under the curve of 0.87. Two signatures incorporating CD27 expression did not distinguish between recently and remotely acquired LTBI. Interestingly, the TNF-α-only TEFF signature in participants with recently acquired LTBI was more similar to that in participants with tuberculosis than that in participants with remotely acquired LTBI, suggesting that recently acquired LTBI is immunologically more similar to tuberculosis than remotely acquired LTBI. These findings reveal marked biological heterogeneity underlying the clinically homogeneous phenotype of LTBI, providing a rationale for immunological risk stratification to improve targeting of LTBI treatment.

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Timing and Targeting of Treatment in Left Ventricular Hypertrophy.

In most clinical cases, left ventricular hypertrophy (LVH) occurs over time from persistent cardiac stress. At the molecular level, this results in both transient and long-term changes to metabolic, sarcomeric, ion handling, and stress signaling pathways. Although this is initially an adaptive change, the mechanisms underlying LVH eventually lead to maladaptive changes including fibrosis, decreased cardiac function, and failure. Understanding the regulators of long-term changes, which are largely driven by transcriptional remodeling, is a crucial step in identifying novel therapeutic targets for preventing the downstream negative effects of LVH and treatments that could reverse or prevent it. The development of effective therapeutics, however, will require a critical understanding of what to target, how to modify important pathways, and how to identify the stage of pathology in which a specific treatment should be used.

Phenotypic Translation of the Disc1 Network Highlights the Role of the Nde1 Locus, with Pharmacological Implications

Previous studies in a Finnish family cohort for schizophrenia have observed significant association with haplotypes and SNPs from five genes within the DISC1 network: DISC1, NDE1, NDEL1, PDE4B and PDE4D. Here, in sub-samples of these Finnish families, we utilize gene expression levels and psychoactive medication use, in order to translate the role of the DISC1 network into biological consequences and potential treatment implications. Genome wide gene expression levels were determined using the Illumina HumanHT-12 v4 Expression BeadChip, in 63 individuals from 18 families, whilst prescription medication information has been collected over a ten year period for all 931 affected individuals. Analysis of the gene expression data, demonstrated that the NDE1 SNP rs2242549 was associated, at the false discovery rate p-value threshold of 0.05, with changes in a large number of probes (n = 1,363). Notably, a significant number of the genes altered (268 out of 1,250) are also predicted to be targets of microRNA 484, which is located on a 5’ non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant association to early cessation of psychoactive medications, specifically a genotype by gender interaction significantly associated with use of CYP2C19 metabolised medications. Furthermore, in a cell culture system, it could be demonstrated that miR-484 can affect the expression of CYP2C19. Together, these findings suggest that mutations at the NDE1 locus may alter risk to mental illness, at least in part through the functional modification of miR-484, and that such modification also alters treatment response to specific psychoactive medications, leading to the potential for the NDE1 locus to be used to assist in the targeting of treatment for psychiatric illness.

Accelerating Translational Research through Open Science: The Neuro Experiment.

Translational research is often afflicted by a fundamental problem: a limited understanding of disease mechanisms prevents effective targeting of new treatments. Seeking to accelerate research advances and reimagine its role in the community, the Montreal Neurological Institute (Neuro) announced in the spring of 2016 that it is launching a five-year experiment during which it will adopt Open Science—open data, open materials, and no patenting—across the institution. The experiment seeks to examine two hypotheses. The first is whether the Neuro’s Open Science initiative will attract new private partners. The second hypothesis is that the Neuro’s institution-based approach will draw companies to the Montreal region, where the Neuro is based, leading to the creation of a local knowledge hub. This article explores why these hypotheses are likely to be true and describes the Neuro’s approach to exploring them.