Summary
Immune tolerance induction (ITI) can overcome inhibitory factor VIII (FVIII) antibodies in haemophilia A patients receiving FVIII replacement therapy. The objective was to evaluate the use of ...sucrose‐formulated, full‐length recombinant FVIII (rFVIII‐FS) for ITI therapy. Patients (<8 years at ITI start) with severe haemophilia A and a peak inhibitor titre >5 Bethesda units (BU) who underwent ITI with any rFVIII‐FS dose for ≥9 months (or until success) were eligible for this retrospective study. Efficacy analyses included descriptions of ITI treatment regimens and outcomes; ITI success was determined solely at the discretion of the investigator. Safety analyses included assessment of adverse events. Of 51 enrolled patients, 32 high dose (≥85 IU kg−1 day−1), n = 21; low dose, n = 11 were eligible for analysis. ITI was successful in 69% (22/32) of patients (high dose, 66.7%; low dose, 72.7%) after a median of 1.4 years (range, 0.1–3.6 years). Influencing factors for ITI success were start of ITI <1 year after inhibitor detection and an inhibitor titre <10 BU at ITI start. All patients successfully tolerized with ITI continued to receive rFVIII‐FS prophylaxis as maintenance therapy, with no inhibitor recurrence from the end of ITI until study enrolment. Use of rFVIII‐FS for ITI was effective and well tolerated; success rates were similar to those in published studies.
Antidepressants are widely prescribed, but their efficacy relative to placebo is modest, in part because the clinical diagnosis of major depression encompasses biologically heterogeneous conditions. ...Here, we sought to identify a neurobiological signature of response to antidepressant treatment as compared to placebo. We designed a latent-space machine-learning algorithm tailored for resting-state electroencephalography (EEG) and applied it to data from the largest imaging-coupled, placebo-controlled antidepressant study (n = 309). Symptom improvement was robustly predicted in a manner both specific for the antidepressant sertraline (versus placebo) and generalizable across different study sites and EEG equipment. This sertraline-predictive EEG signature generalized to two depression samples, wherein it reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation treatment outcome. Furthermore, we found that the sertraline resting-state EEG signature indexed prefrontal neural responsivity, as measured by concurrent transcranial magnetic stimulation and EEG. Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression.
A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This ...heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD.
Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone-exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the "normative population." Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles.
The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data.
The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.
The authors sought to identify brain regions whose frequency-specific, orthogonalized resting-state EEG power envelope connectivity differs between combat veterans with posttraumatic stress disorder ...(PTSD) and healthy combat-exposed veterans, and to determine the behavioral correlates of connectomic differences.
The authors first conducted a connectivity method validation study in healthy control subjects (N=36). They then conducted a two-site case-control study of veterans with and without PTSD who were deployed to Iraq and/or Afghanistan. Healthy individuals (N=95) and those meeting full or subthreshold criteria for PTSD (N=106) underwent 64-channel resting EEG (eyes open and closed), which was then source-localized and orthogonalized to mitigate effects of volume conduction. Correlation coefficients between band-limited source-space power envelopes of different regions of interest were then calculated and corrected for multiple comparisons. Post hoc correlations of connectomic abnormalities with clinical features and performance on cognitive tasks were conducted to investigate the relevance of the dysconnectivity findings.
Seventy-four brain region connections were significantly reduced in PTSD (all in the eyes-open condition and predominantly using the theta carrier frequency). Underconnectivity of the orbital and anterior middle frontal gyri were most prominent. Performance differences in the digit span task mapped onto connectivity between 25 of the 74 brain region pairs, including within-network connections in the dorsal attention, frontoparietal control, and ventral attention networks.
Robust PTSD-related abnormalities were evident in theta-band source-space orthogonalized power envelope connectivity, which furthermore related to cognitive deficits in these patients. These findings establish a clinically relevant connectomic profile of PTSD using a tool that facilitates the lower-cost clinical translation of network connectivity research.
The understanding and treatment of psychiatric disorders, which are known to be neurobiologically and clinically heterogeneous, could benefit from the data-driven identification of disease subtypes. ...Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional connectivity patterns, prominently within the frontoparietal control network and the default mode network. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets of patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis.
A PARADOX IN POLARIZATION? Toll, Benjamin T.
World affairs (Washington),
March 2019, Letnik:
182, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Members of the public are often left choosing between two extreme candidates who will not represent the moderate, aggregate, public effectively. Cross-pressured members of the U.S. Congress serve a ...constituency that votes for the opposite party at the national level. If there is any group of representatives that have an incentive to moderate their voting behavior, it is cross-pressured members. In this article, I show that cross-pressured members are more moderate than the average member of their party. This could provide constraints on rampant partisanship in the form of districts that are comfortable electing a representative of one party and voting for the president of the other. However, I show that these members are significantly less likely to be reelected. Thus a paradox exists in which cross-pressured members who moderate their voting behavior are no more likely to be rewarded for behaving the way citizens claim they want to represent.
Los miembros del público a menudo tienen la elección entre dos candidatos extremos que no representarán al público moderado y agregado de manera efectiva. Los miembros del Congreso sometidos a presión cruzada sirven a un distrito electoral que vota por el partido opuesto a nivel nacional. Si hay algún grupo de representantes que tienen un incentivo para moderar su comportamiento de voto, se trata de miembros con presiones cruzadas. En este documento, muestro que los miembros con presiones cruzadas son más moderados que el miembro promedio de su partido. Esto podría restringir el partidismo desenfrenado en forma de distritos que se sienten cómodos al elegir a un representante de un partido y votar por el presidente del otro. Sin embargo, estos miembros tienen una probabilidad significativamente menor de ser reelegidos. Por lo tanto, existe una paradoja en la que los miembros con presiones cruzadas que moderan su comportamiento de voto no tienen más probabilidades de ser recompensados por comportarse de la manera en que los ciudadanos dicen que quieren representar.
公众经常会在两位极端的候选人中做出选择, 而这两位候选人并不能有效地代表普遍的温和派民众。交叉压力下的国会议员服务于在全国范围内给敌对政党投票的选区民众。存在缓和民众投票行为动机的国会议员都是处于交叉压力之下的。本文笔者表明, 交叉压力下的议员比自身党内的其他普通议员态度更为温和。这可能会限制以乐于选举一个政党的代表却投票给另一个政党领导的地区选民形式存在的党派关系。然而, 这些议员获得连任的可能性要小得多。因此, 悖论便就此产生, 那些交叉压力下想要缓和投票行为的议员不太可能因为按照民众想要代表的方式行事而受到奖励。
A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined ...subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.
Introduction
Human parainfluenza virus type 3 (HPIV-3) causes significant morbimortality in immunocompromised patients. Outbreaks of severe pneumonitis have been previously described in this setting.
...Materials and methods
Retrospective observational study in children diagnosed with acute leukemia and a documented HPIV-3 infection in the context of a nosocomial outbreak occurred in a single center.
Result
During summer 2012, an HPIV-3 infection was detected in six hospitalized children with acute leukemia. All the patients had respiratory symptoms and one of them suffered from parotitis.
Conclusion
Early diagnoses using multiplex real-time polymerase chain reaction (PCR) let us control this outbreak. A phylogenetic analysis confirmed person-to-person transmission of a single HPIV-3 variant.
Depression has a chronic and recurrent course often with early onset and is the leading cause of disability worldwide. In contrast to diagnoses for other conditions which rely on precise medical ...tests, the diagnosis of depression still focuses exclusively on symptom reports. As a result, heterogeneous patient groups are included under broad categories. Furthermore, in the absence of companion diagnostic tests, choosing specific treatments for patients remains imprecise with only one-third of patients entering remission with initial treatment, with others requiring multiple intervention steps to achieve remission. In addition to improving treatment outcomes, disease prevention is essential to reduce overall disease burden. Adolescence is a critical window where complex emotional, social, familial, and biological shifts may predispose to lifelong depression. Thus, personalized medicine, integrating individual variability in genes, brain function, and clinical phenotypes, can offer a comprehensive approach to provide precise diagnosis, novel drug development, optimal treatment assignment, and prevention of illness and its associated burden. Texas Resilience Against Depression study (T-RAD) encompasses two natural history, longitudinal (10 + years), prospective studies (D2K and RAD), each enrolling 2500 participants. The D2K study follows participants (ages 10 years and older) who have a current or past diagnosis of depression or bipolar disorder. The RAD study follows participants aged 10–24 years who are at risk for depression but not yet suffering from the disease. The T-RAD study will help to uncover the socio-demographic, lifestyle, clinical, psychological, and neurobiological factors that contribute to mood disorder onset, recurrence, progression, and differential treatment response.
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