Notes

Affiliation of microbe group types, well-designed microbial processes and also respiratory disease in cystic fibrosis air passage.
Personality disorder (PD) symptoms in a parent generation may confer risk for problems in future generations, but intergenerational transmission has not been studied beyond parent-child effects. We examined the generational transfer of risk associated with PDs using structural models of grandparent personality pathology and grandchild psychopathology among 180 adults (M age =66.9), 218 of their children (M age =41.2), and 337 of their grandchildren (M age =10.5). We found evidence for general and heterotypic domain-specific transmission. Specifically, broad grandparent personality pathology was associated with broad grandchild psychopathology (B=.15, 95% CI [-.01, .31]); at the domain level, grandparent internalizing personality pathology was associated with grandchild externalizing psychopathology (B =.06, 95% CI [.01, .12]). Neither association was significantly mediated by parental personality pathology. These findings indicate that personality pathology in one generation confers risk for psychopathology across subsequent generations. Such intergenerational transmission operates across broad, rather than specific (i.e., individual disorder) psychopathology domains.
This review seeks to explore blood-based biomarkers with the potential for clinical implementation.

Emerging non-proteomic biomarkers hold promise for more accurate diagnostic and prognostic capabilities, especially in the subacute to chronic phase of TBI recovery. Further, there is a growing understanding of the overlap between TBI-related and Dementia-related blood biomarkers.

Given the significant heterogeneity inherent in the clinical diagnosis of Traumatic Brain Injury (TBI), there has been an exponential increase in TBI-related biomarker research over the past two decades. While TBI-related biomarker assessments include both cerebrospinal fluid analysis and advanced neuroimaging modalities, blood-based biomarkers hold the most promise to be non-invasive biomarkers widely available to Brain Injury Medicine clinicians in diverse practice settings. In this article, we review the most relevant blood biomarkers for the field of Brain Injury Medicine, including both proteomic and non-proteomic blood biomarkers, biomarkers of cerebral microvascular injury, and biomarkers that overlap between TBI and Dementia.
Given the significant heterogeneity inherent in the clinical diagnosis of Traumatic Brain Injury (TBI), there has been an exponential increase in TBI-related biomarker research over the past two decades. While TBI-related biomarker assessments include both cerebrospinal fluid analysis and advanced neuroimaging modalities, blood-based biomarkers hold the most promise to be non-invasive biomarkers widely available to Brain Injury Medicine clinicians in diverse practice settings. In this article, we review the most relevant blood biomarkers for the field of Brain Injury Medicine, including both proteomic and non-proteomic blood biomarkers, biomarkers of cerebral microvascular injury, and biomarkers that overlap between TBI and Dementia.
The Veterans Health Administration (VHA) initiated a system-wide redesign in 2011 toward a patient-centered approach called the Whole Health System (WHS) of care. Education of VHA clinical staff in WHS-informed care, Whole Health Clinical Care (WHCC), is one critical element of this redesign effort. At a minimum, WHCC education should address core competencies for clinicians and be considered satisfactory for learners. This is the first study to evaluate learner satisfaction and perceived achievement of course objectives in WHCC that incorporated active learning strategies.

A large VA Healthcare System developed an in-person workshop focused on WHCC that used multiple active learning activities. These activities included case presentations, role playing, experiential learning, and group discussion.

Sixty-two interprofessional staff attended the workshop in November 2019. Forty (64.50%) participants completed post-workshop surveys within 30days. Data suggest participants were highly satisfied with the workshop and that they successfully met stated learning objectives.

We call on VHA and private-sector hospitals to train clinical staff in WHCC that incorporates use of active learning strategies.
We call on VHA and private-sector hospitals to train clinical staff in WHCC that incorporates use of active learning strategies.
Irritant contact dermatitis is the most common form of contact dermatitis and the most common occupational skin disease. This review provides a comprehensive summary of the endogenous and exogenous factors that play a role in the pathogenesis of irritant contact dermatitis.

In conjunction with avoidance of irritants, barrier protection, and regular application of moisturizers, management now emphasizes the importance of primary prevention through educational initiatives in high-risk workplaces.

The diagnosis of irritant contact dermatitis is often difficult, as there is no confirmatory test, and it is often a default diagnosis after allergic contact dermatitis has been excluded. Early recognition, prevention, and treatment are vital in management, especially in the occupational setting.
The diagnosis of irritant contact dermatitis is often difficult, as there is no confirmatory test, and it is often a default diagnosis after allergic contact dermatitis has been excluded. Early recognition, prevention, and treatment are vital in management, especially in the occupational setting.Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and in vivo activity. Aptamers as carriers for siRNA approaches were created including a cancer targeting nucleolin aptamer Ncl-OPN siRNA and a myeloid targeting CpG oligodeoxynucleotide (ODN)-OPN siRNA conjugate. These aptamers were selected as therapeutic leads based on 70-90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. In established immune competent 344SQ lung cancer and 4T1B2b breast cancer models, these aptamers, including in combination, demonstrate therapeutic activity by inhibiting tumor growth. The Ncl-OPN siRNA aptamer demonstrated efficacy in an immune competent orthotopic glioma model administered systemically secondary to the ability of the aptamer to access the glioma TME. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers that are internalized by specific cell types and suppress OPN expression once internalized may have clinical potential in cancer treatment.A wide spectrum of SLC26A4 mutations causes Pendred syndrome and enlarged vestibular aqueduct, both associated with sensorineural hearing loss (SNHL). A splice-site mutation, c.919-2A>G (A-2G), which is common in Asian populations, impairs the 3' splice site of intron 7, resulting in exon 8 skipping during pre-mRNA splicing and a subsequent frameshift that creates a premature termination codon in the following exon. Currently, there is no effective drug treatment for SHNL. For A-2G-triggered SNHL, molecules that correct mis-splicing of the mutant hold promise to treat the disease. Antisense oligonucleotides (ASOs) can promote exon inclusion when targeting specific splicing silencers. Here, we systematically screened a large number of ASOs in a minigene system and identified a few that markedly repressed exon 8 skipping. A lead ASO, which targets a heterogeneous nuclear ribonucleoprotein (hnRNP) A1/A2 intronic splicing silencer (ISS) in intron 8, promoted efficient exon 8 inclusion in cultured peripheral blood mononuclear cells derived from two homozygous patients. In a partially humanized Slc26a4 A-2G mouse model, two subcutaneous injections of the ASO at 160 mg/kg significantly rescued exon 8 splicing in the liver. Our results demonstrate that the ISS-targeting ASO has therapeutic potential to treat genetic hearing loss caused by the A-2G mutation in SLC26A4.[This retracts the article DOI 10.1016/j.omtn.2020.01.016.].We investigated the feasibility of utilizing an exon-skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin protein expression and GTPase activating protein (GAP)-related domain (GRD) function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function, which was confirmed by in vitro assessments utilizing an Nf1 cDNA-based functional screening system. Selleck Etomoxir Skipping of exons 17 or 52 fit our criteria, as minimal effects on protein expression and GRD activity were noted. Antisense phosphorodiamidate morpholino oligomers (PMOs) were utilized to skip exon 17 in human cell lines with patient-specific pathogenic variants in exon 17, c.1885G>A, and c.1929delG. PMOs restored functional neurofibromin expression. To determine the in vivo significance of exon 17 skipping, we generated a homozygous deletion of exon 17 in a novel mouse model. Mice were viable and exhibited a normal lifespan. Initial studies did not reveal the presence of tumor development; however, altered nesting behavior and systemic lymphoid hyperplasia was noted in peripheral lymphoid organs. Alterations in T and B cell frequencies in the thymus and spleen were identified. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with pathogenic variants in exon 17, as homozygous deletion of exon 17 is consistent with at least partial function of neurofibromin.
Abnormal involuntary movement of paralyzed upper limb during yawning is a rare phenomenon termed as parakinesia brachialis oscitans.

We describe a 59-year-old gentleman with abnormal involuntary movement of paralyzed right upper limb during yawning 2 weeks following ischemic stroke of left middle cerebral artery territory.

This is a rare post-stroke phenomenon and its pathophysiological mechanism is poorly understood but this entity highlights possible preserved extrapyramidal pathway which might help in rehabilitating stroke survivors.
This is a rare post-stroke phenomenon and its pathophysiological mechanism is poorly understood but this entity highlights possible preserved extrapyramidal pathway which might help in rehabilitating stroke survivors.
Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry.

Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature.

Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing.
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