Search

ABSTRACTInternational studies examining dysphagia management have identified that a degree of practice variability exists globally, with multiple factors within the local health service context influencing the nature of services. Understanding current practices and service inefficiencies is a foundational step for service optimization. Thus, this study aimed to understand service characteristics and issues associated with adult dysphagia service provision within acute and subacute settings in Singapore. Two online anonymous surveys were conducted with: (a) managers to explore practice documents used to guide dysphagia services, and (b) speech-language pathologists (SLPs) to understand dysphagia practices and service issues. Data were analyzed using descriptive statistics and content analysis. Responses from 12 managers and 68 SLPs working in acute and subacute settings were analyzed. There was a lack of national practice documents to guide dysphagia clinical training and service provision, and services were generally guided by internal documents. Despite this, dysphagia services were similar across acute and subacute settings. However, differences between settings were identified in screening and instrumental assessments services, perceived rehabilitation intensity, perceived rehabilitation adherence among patients, and extent of challenges with onward referrals. Whilst Singapore’s dysphagia services were largely aligned with other countries, challenges unique to the Singapore context was found relating to enteral feeding management, language barrier, financing framework, and care transitions. These findings build on the knowledge of dysphagia practices internationally, and provide direction for service optimization in Singapore.

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer’s disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5′UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n= 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p= 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p= 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p= 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p= 0.026 and p= 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

IMPORTANCE: Guidelines recommend seizure prophylaxis for early posttraumatic seizures (PTS) after severe traumatic brain injury (TBI). Use of antiseizure medications for early seizure prophylaxis after mild or moderate TBI remains controversial. OBJECTIVE: To determine the association between seizure prophylaxis and risk reduction for early PTS in mild and moderate TBI. DATA SOURCES: PubMed, Google Scholar, and Web of Science (January 1, 1991, to April 18, 2023) were systematically searched. STUDY SELECTION: Observational studies of adult patients presenting to trauma centers in high-income countries with mild (Glasgow Coma Scale [GCS], 13-15) and moderate (GCS, 9-12) TBI comparing rates of early PTS among patients with seizure prophylaxis with those without seizure prophylaxis. DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) reporting guidelines were used. Two authors independently reviewed all titles and abstracts, and 3 authors reviewed final studies for inclusion. A meta-analysis was performed using a random-effects model with absolute risk reduction. MAIN OUTCOME MEASURES: The main outcome was absolute risk reduction of early PTS, defined as seizures within 7 days of initial injury, in patients with mild or moderate TBI receiving seizure prophylaxis in the first week after injury. A secondary analysis was performed in patients with only mild TBI. RESULTS: A total of 64 full articles were reviewed after screening; 8 studies (including 5637 patients) were included for the mild and moderate TBI analysis, and 5 studies (including 3803 patients) were included for the mild TBI analysis. The absolute risk reduction of seizure prophylaxis for early PTS in mild to moderate TBI (GCS, 9-15) was 0.6% (95% CI, 0.1%-1.2%; P = .02). The absolute risk reduction for mild TBI alone was similar 0.6% (95% CI, 0.01%-1.2%; P = .04). The number needed to treat to prevent 1 seizure was 167 patients. CONCLUSION AND RELEVANCE: Seizure prophylaxis after mild and moderate TBI was associated with a small but statistically significant reduced risk of early posttraumatic seizures after mild and moderate TBI. The small absolute risk reduction and low prevalence of early seizures should be weighed against potential acute risks of antiseizure medications as well as the risk of inappropriate continuation beyond 7 days.

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.

OBJECTIVE--To assess the quality of hypertension care in patients with type 2 diabetes in general practice and identify physician, organizational, and patient factors associated with sub-optimal care. RESEARCH DESIGN AND [...]

This paper analyzes the role of Corporate Social Responsibility (CSR) in the hotel sector of Mérida State (Venezuela) and its contribution to the sociocultural dimension of local development. A theoretical framework is presented that supports the subsequent empirical analysis. Summary is made of the public policies related to CSR and the tourism sector, and the characteristics of the State of Merida where the tourism activity that is going to be analyzed is carried out. Next, the empirical part is developed. The managers of the hotels were surveyed, using a questionnaire adapted from indicators of the ETHOS Institute. Average values of the different items are obtained by dimensions, themes and indicators and a logistic regression model is applied. The Governance and Management dimension has high compliance with anti-corruption practices. In the Social dimension, three indicators are highly valued (relationship with consumers, monitoring the impact on human rights and relations with employees) and three less valued (support for the development of suppliers, commitment to the community and professional development). Additionally, three aspects of CSR contribute to the sociocultural dimension (vision and strategy, human rights and sustainable use of resources) and represent 58% of the larger hotels, with most category, and longest seniority.

An investigation into the effect of order batching in an order picking system that uses a unidirectional cyclical picking line forms the main focus of this paper. The three main actions of pickers are to walk, pick and prepare cartons. The total amount of work for the last two actions remains constant, rendering the minimisation of walking distance as the only objective when minimising the total picking effort. Batches are formed to minimise walking distance. The question thus arises, what is the total time saving before and after batching? This picking system is modelled with a discrete event simulation. Historical data were compared to the output of the simulation for validation of the simulation. It showed that the simulation represents the real world picking system satisfactorily. The simulation runs also show that the order batching heuristics that aim at minimising walking distance reduce the overall picking time by up to 21%.

ObjectiveTo examine associations of patient characteristics and treatment quantity delivered during inpatient spinal cord injury (SCI) rehabilitation with outcomes at 5 years post-injury and compare them to the associations found at 1 year post-injury.DesignObservational study using Practice-Based Evidence research methodology in which clinicians documented treatment details. Regression modeling was used to predict outcomes.SettingFive inpatient SCI rehabilitation centers in the US.ParticipantsParticipants were 792 SCIRehab participants who were >12 years of age, gave informed consent, and completed both a 1-year and 5-year post-injury interview.Outcome MeasuresOutcome data were derived from Spinal Cord Injury Model Systems (SCIMS) follow-up interviews at 5 years post-injury and, similar to the 1-year SCIMS outcomes, included measures of physical independence, societal participation, life satisfaction, and depressive symptoms, as well as place of residence, school/work attendance, rehospitalization, and presence of pressure ulcers.ResultsConsistent with 1-year findings, patient characteristics continue to be strong predictors of outcomes 5-years post-injury, although several variables add to the prediction of some of the outcomes. More time in physical therapy and therapeutic recreation were positive predictors of 1-year outcomes, which held less true at 5 years. Greater time spent with psychology and social work/case management predicted greater depressive symptomatology 5-years post-injury. Greater clinician experience was a predictor at both 1- and 5 -years, although the related positive outcomes varied across years.ConclusionVarious outcomes 5-years post-injury were primarily explained by pre-and post-injury characteristics, with little additional variance offered by the quantity of treatment received during inpatient rehabilitation.

Undertreatment of risk factors in patients with type 2 diabetes is common. We assessed the influence of elevated levels of blood pressure, total cholesterol, and A1C on decisions of Dutch [...]

IMPORTANCE: Traumatic brain injury (TBI) leads to 2.9 million visits to US emergency departments annually and frequently involves a disorder of consciousness (DOC). Early treatment, including withdrawal of life-sustaining therapies and rehabilitation, is often predicated on the assumed worse outcome of disrupted consciousness. OBJECTIVE: To quantify the loss of consciousness, factors associated with recovery, and return to functional independence in a 31-year sample of patients with moderate or severe brain trauma. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed patients with TBI who were enrolled in the Traumatic Brain Injury Model Systems National Database, a prospective, multiyear, longitudinal database. Patients were survivors of moderate or severe TBI who were discharged from acute hospitalization and admitted to inpatient rehabilitation from January 4, 1989, to June 19, 2019, at 1 of 23 inpatient rehabilitation centers that participated in the Traumatic Brain Injury Model Systems program. Follow-up for the study was through completion of inpatient rehabilitation. EXPOSURES: Traumatic brain injury. MAIN OUTCOMES AND MEASURES: Outcome measures were Glasgow Coma Scale in the emergency department, Disability Rating Scale, posttraumatic amnesia, and Functional Independence Measure. Patient-related data included demographic characteristics, injury cause, and brain computed tomography findings. RESULTS: The 17 470 patients with TBI analyzed in this study had a median (interquartile range [IQR]) age at injury of 39 (25-56) years and included 12 854 male individuals (74%). Of these patients, 7547 (57%) experienced initial loss of consciousness, which persisted to rehabilitation in 2058 patients (12%). Those with persisting DOC were younger; had more high-velocity injuries; had intracranial mass effect, intraventricular hemorrhage, and subcortical contusion; and had longer acute care than patients without DOC. Eighty-two percent (n = 1674) of comatose patients recovered consciousness during inpatient rehabilitation. In a multivariable analysis, the factors associated with consciousness recovery were absence of intraventricular hemorrhage (adjusted odds ratio [OR], 0.678; 95% CI, 0.532-0.863; P = .002) and intracranial mass effect (adjusted OR, 0.759; 95% CI, 0.595-0.968; P = .03). Functional improvement (change in total functional independence score from admission to discharge) was +43 for patients with DOC and +37 for those without DOC (P = .002), and 803 of 2013 patients with DOC (40%) became partially or fully independent. Younger age, male sex, and absence of intraventricular hemorrhage, intracranial mass effect, and subcortical contusion were associated with better functional outcome. Findings were consistent across the 3 decades of the database. CONCLUSIONS AND RELEVANCE: This study found that DOC occurred initially in most patients with TBI and persisted in some patients after rehabilitation, but most patients with persisting DOC recovered consciousness during rehabilitation. This recovery trajectory may inform acute and rehabilitation treatment decisions and suggests caution is warranted in consideration of withdrawing or withholding care in patients with TBI and DOC.

ABSTRACTThis study identifies those market segments that frequent state parks in Florida and, in particular, determines those segmentation “clusters” with a best fit for frequency of visitation, accommodation, and age. Two-Step Cluster Analysis and CHAID approaches to the determination of market segmentation are used. This study demonstrates the precision and multi-tree nature of CHAID analysis in that it offers additional levels of variation and distinctiveness for those marketing and managing tourism generally, and in the specific context of state parks. Rather than managing a homogenous “rural tourist”, through CHAID analysis, state parks can benefit from the fine-tuning of marketing messages, the more effective provision and location of accommodation stock, and enhanced efforts to attract out-of-state visitors.

Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Aluretrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.

Crucial decisions involving cell fate and connectivity that shape the distinctive development of the human brain occur in the embryonic and fetal stages—stages that are difficult to access and investigate in humans. The last decade has seen an impressive increase in resources—from atlases and databases to biological models—that is progressively lifting the curtain on this critical period. In this review, we describe the current state of genomic, transcriptomic, and epigenomic datasets charting the development of normal human brain with a particular focus on recent single-cell technologies. We discuss the emergence of brain organoids generated from pluripotent stem cells as a model to compensate for the limited availability of fetal tissue. Indeed, comparisons of neural lineages, transcriptional dynamics, and noncoding element activity between fetal brain and organoids have helped identify gene regulatory networks functioning at early stages of brain development. Altogether, we argue that large multi-omics investigations have pushed brain development into the “big data” era, and that current and future transversal approaches needed to leverage both fetal brain and organoid resources promise to answer major questions of brain biology and psychiatry.

In this paper game theory is applied to maximise profit by identifying the optimal channel to collect and remanufacture used products in an electronic equipment retail network context. Without a detailed method to compute reverse logistics cost, the most profitable channel may not be chosen. Therefore, the main aim of the paper is to realistically model manufacturer, retailer and third-party as three different collection channel options to compete over return rates. A more realistic and detailed method to compute the reverse logistics cost is introduced because it is crucial in determining the most profitable channel. In the non-cooperative and cooperative version of the game the manufacturer gains the highest and the retailer the second highest payoff, since both players benefit from selling new products. Furthermore, the third-party can turn the collection of used products into a successful business by using synergy effects between different clients within the logistics network. There is consistency between the results of the non-cooperative and the cooperative version of the game. Moreover, if fines are imposed externally (for example by legislation), the best option is to cooperate in the grand coalition. Subcontracting the third-party yields the highest payoffs due to their lowest reverse logistics cost.

ABSTRACTIncreases in population ageing and urbanization have led to the development of age-friendly cities. While much has been done to integrate the needs of younger, healthier older adults, little research has examined the needs of the oldest-old. This phenomenological study explored the lived experience of 10 community-dwelling individuals, aged 80 years and older, using community support and health services. Three central themes emerged: individual circumstances, personal compensatory mechanismsand community design and structure. Numerous implications for age-friendly development were highlighted: (1) functional ability rather than chronological age should be considered in age-friendly planning, (2) informal social community supports are very important for those in advanced age; age-friendly city planners must consider individuals in advanced age who are on the edge of losing their independence, and whose loss of independence may be hastened or delayed based on informal social supports available, (3) community design that recognizes and integrates structures to support the needs of frailer older adults may provide a protective buffer to enable these individuals to remain in their homes longer, and (4) socially isolated frail older adults are difficult to reach; innovative strategies are required to ensure their unique needs are discovered and incorporated in community planning.

Objectives: To assess the risk of dental anomaly presentation in permanent teeth in a group of Colombian children with nonsyndromic cleft lip and palate (NSCLP) and to determine the frequency of the anomalies according to the cleft type.Methods: An analytical matched case–control study was conducted with 210 controls and 210 patients with NSCLP. The patients were classified into 3 groups: complete right unilateral cleft lip and palate (RCLP), complete left unilateral cleft lip and palate (LCLP), and complete bilateral cleft lip and palate (BCLP). Univariate and multivariate Poisson regression models were used to analyze paired samples (Bonferroni adjustment, P≤ .002).Results: A high risk of finding agenesis of the maxillary lateral incisors, supernumerary teeth, microdontia of the maxillary lateral incisors, and rotation of the maxillary central incisors adjacent to the cleft (P< .0001) was observed in the patients with NSCLP. One or more dental anomalies were found in 98% of patients with BCLP, in 96% of those with LCLP, and in 87% of those with RCLP. Most of the anomalies were located on the cleft area. The incidence relative risk (IRR) of anomalies was highest in patients with BCLP (IRR: 10.5; 95% confidence interval [CI]: 6.76-16.3), followed by in those with LCLP (IRR: 8.51; 95% CI: 5.64-12.8).Conclusions: Most dental anomalies were found in the cleft area; this was expected because the cleft area was the most affected in the patients included in this study.

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200–400 mosaic SNVs per cell in three human fetal brains (15–21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to ∼14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in ∼10% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (∼6200 vs. ∼4000 bp), implying that they may have similar functional consequences.

To understand the transformations of mercury (Hg) species in the subsurface of a HgCl2-contaminated former industrial site in southwest Germany, Hg isotope analysis was combined with an investigation of Hg forms by a four-step sequential extraction protocol (SEP) and pyrolytic thermodesorption. Data from two soil cores revealed that the initial HgCl2was partly reduced to metallic Hg(0) and that Hg forms of different mobility and oxidation state coexist in the subsurface. The most contaminated sample (K2-8, 802 mg kg–1Hg) had a bulk δ202Hg value of around −0.43 ± 0.06‰ (2SD), similar to published average values for industrial Hg sources. Other sample signatures varied significantly with depth and between SEP pools. The most Hg-rich samples contained mixtures of Hg(0) and Hg(II) phases, and the water-extractable, mobile Hg pool exhibited heavy δ202Hg values of up to +0.18‰. Sequential water extracts revealed slow dissolution kinetics of mobile Hg pools, continuously releasing isotopically heavy Hg into solution. This was further corroborated by heavy δ202Hg values of groundwater samples. Our results demonstrate that the Hg isotope signature of an industrial contamination source can be significantly altered during the transformations of Hg species in the subsurface, which complicates source tracing applications but offers the possibility of using Hg isotopes as process tracers in contaminated subsurface systems.

Understanding common biological consequences of heterogenous mutations in complex polygenic conditions is challenging. In this issue of Cell Stem Cell, Cederquist et al. (2020) implement an in vitropooled assay where 30 high-confidence ASD mutations engineered in subclones of a human pluripotent stem cell line can be investigated in parallel to reveal their effects on prefrontal cortex neurogenesis.

The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluate and compare the efficacy of two cognitive rehabilitation interventions (Memory and Attention Adaptation Training (MAAT) and Attention Builders Training (ABT)), with and without pharmacological enhancement (ie, with methylphenidate (MPH) or placebo), for treating persistent cognitive problems after traumatic brain injury (TBI). Adults with a history of TBI at least 4 months before study enrollment with either objective cognitive deficits or subjective cognitive complaints were randomized to receive MPH or placebo and MAAT or ABT, yielding four treatment combinations: MAAT/MPH (N=17), ABT/MPH (N=19), MAAT/placebo (N=17), and ABT/placebo (N=18). Assessments were conducted pre-treatment (baseline) and after 6 weeks of treatment (post treatment). Outcome measures included scores on neuropsychological measures and subjective rating scales. Statistical analyses used linear regression models to predict post-treatment scores for each outcome variable by treatment type, adjusting for relevant covariates. Statistically significant (P<0.05) treatment-related improvements in cognitive functioning were found for word-list learning (MAAT/placebo>ABT/placebo), nonverbal learning (MAAT/MPH>MAAT/placebo and MAAT/MPH>ABT/MPH), and auditory working memory and divided attention (MAAT/MPH>ABT/MPH). These results suggest that combined treatment with metacognitive rehabilitation (MAAT) and pharmacotherapy (MPH) can improve aspects of attention, episodic and working memory, and executive functioning after TBI.

Supplemental Digital Content is available in the text.

We currently have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that postmortem and imaging studies can only measure the postnatal status quo and offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) should, in principle, prove powerful for elucidating the pathways that give rise to neurodevelopmental disorders. hiPSCs are embryonic-stem-cell-like cells that can be derived from somatic cells. They retain the unique genetic signature of the individual from whom they were derived, and thus enable researchers to recapitulate that individual's idiosyncratic neural development in a dish. In the case of individuals with disease, we can re-enact the disease-altered trajectory of brain development and examine how and why phenotypic and molecular abnormalities arise in these diseased brains. Here, we review hiPSC biology and possible experimental designs when using hiPSCs to model disease. We then discuss existing hiPSC models of neurodevelopmental disorders. Our hope is that, as some studies have already shown, hiPSCs will illuminate the pathophysiology of developmental disorders of the CNS and lead to therapeutic options for the millions that are affected by these conditions.

Before the 20th-century, a good many couples married out of necessity: To breed enough offspring to help work the land. Originating in Europe, wedding traditions such as throwing rice and [...]

Parting gifts. You know them as party goodie (a.k.a loot) bags. They're a must for even the most modest child's party. Goodie bags are pint-sized versions of adult favors - [...]

Few studies have been conducted to understand post-zygotic accumulation of mutations in cells of the healthy human body. We reprogrammed 32 skin fibroblast cells from families of donors into human induced pluripotent stem cell (hiPSC) lines. The clonal nature of hiPSC lines allows a high-resolution analysis of the genomes of the founder fibroblast cells without being confounded by the artifacts of single-cell whole-genome amplification. We estimate that on average a fibroblast cell in children has 1035 mostly benign mosaic SNVs. On average, 235 SNVs could be directly confirmed in the original fibroblast population by ultradeep sequencing, down to an allele frequency (AF) of 0.1%. More sensitive droplet digital PCR experiments confirmed more SNVs as mosaic with AF as low as 0.01%, suggesting that 1035 mosaic SNVs per fibroblast cell is the true average. Similar analyses in adults revealed no significant increase in the number of SNVs per cell, suggesting that a major fraction of mosaic SNVs in fibroblasts arises during development. Mosaic SNVs were distributed uniformly across the genome and were enriched in a mutational signature previously observed in cancers and in de novo variants and which, we hypothesize, is a hallmark of normal cell proliferation. Finally, AF distribution of mosaic SNVs had distinct narrow peaks, which could be a characteristic of clonal cell selection, clonal expansion, or both. These findings reveal a large degree of somatic mosaicism in healthy human tissues, link de novo and cancer mutations to somatic mosaicism, and couple somatic mosaicism with cell proliferation.

Aim:Details of data quality and how quality issues were solved have not been reported in published comparative effectiveness studies using electronic health record data. Methods:We developed a conceptual framework of data quality assessment and preprocessing and apply it to a study comparing angiotensin-converting enzyme inhibitors with angiotensin receptor blockerss on renal function decline in diabetes patients. Results:The framework establishes a line of thought to identify and act on data issues. The core concept is to evaluate whether data are fit-for-use for research tasks. Possible quality problems are listed through specific signal detections, and verified whether they are true problems. Optimal solutions are selected for the identified problems. Conclusion:This framework can be used in observational studies to improve validity of results.

Aim:To compare effectiveness of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) for protecting Type 2 diabetes mellitus (DM2) patients from renal function decline in a real-world setting. Methods:Retrospective cohort study of new ACEi/ARB users in 2007–2012 in an unselected primary care DM2 population. Outcome is decline in renal function stage (combining estimated glomerular filtration rate and albuminuria). Patients were matched on a propensity score. Extended Cox models with time-varying covariates were used to estimate hazard ratios of outcome. Results:The time to renal function decline for ARB users was slightly, but not significantly longer than for ACEi users (hazard ratio: 0.80; 95 CI: 0.58–1.10; p 0.166). Conclusion:This study did not show significant differences between the classes in preventing renal function decline in DM2 patients in primary care.

Background data: Ganglioneuroma is rare in children and often incidentally discovered. The transperitoneal laparoscopic approach is the surgical choice for most of the surgeons because of the familiar anatomy and the wider working spaces. However, a posterior retroperitoneal approach started to be used in pediatric population demonstrating to be safe and effective. Case presentation: We present a case of a child with radiological finding of a right adrenal mass. Due to the increased risk of having a malignant transformation, a surgical resection was decided using a retroperitoneal approach. The adrenal mass was recognized and completely enucleated. The histopathological examination revealed a GN. Clinical course was uneventful with hospital discharge after 3 days. The outcome was evaluated by ultrasound examination performed 3–6 to 12–24 months and then annually. After 24 months, the patient is completely asymptomatic, and no adrenal masses in both sides have been detected. Conclusions: The posterior retroperitoneoscopy permits a more direct exposure of the adrenal gland, without violating the peritoneum, and a close vision to the main vessels. We believe that this technique is a valid option for pediatric patients with small adrenal lesions.

Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/− heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (P<0.001), 29 of which showed a fold change ≥1.5. Among the differentially expressed genes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/− whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments.

Performance measures are used for assessing quality of care. Higher performance shown by these measures is expected to reflect better care, but little is known whether they predict better patient outcomes.

Of the three major subdivisions of the auditory thalamus, the medial subdivision is the only one that receives a direct projection from the dorsal cochlear nucleus. Those cells in the medial auditory thalamus that receive the projection from the dorsal cochlear nucleus continue to the auditory cortex. A combination of anterograde and retrograde anatomical tracer injections made in the dorsal cochlear nucleus and the auditory cortex respectively, revealed terminal boutons which were directly apposed onto the dendrites and cell bodies of neurons in the medial auditory thalamus. The presence of a monosynaptic pathway, which transfers information from the first relay in the auditory system to the last, suggests that this pathway may rapidly convey very basic information to the auditory cortex.

AbstractContext:Social work and case management (SW/CM) are integral components of acute inpatient spinal cord injury (SCI) rehabilitation. However, evidence is sparse regarding the impact of SW/CM interventions on outcomes. To advance research on SW/CM clinical practice in SCI rehabilitation, SW/CM providers and researchers first must have standard classifications for SW/CM interventions.Background/Objective:To develop a taxonomy (classification) of the various interventions and services that comprise SW/CM.Methods:A group of SW/CM clinicians compiled a list of activities performed as routine practice at the participating rehabilitation facilities. These activities were grouped and defined systematically.Results:The resulting taxonomy includes 8 major activity topics (financial planning, discharge planning, discharge services, supportive counseling, information about and referral to peer/advocacy groups, education about SCI and other relevant topics, information about and referral to community/in-house services, and team conferences), which were further stratified into specific content areas. Interactions with the patient, family, or other team members and resources, along with descriptions of the interactions that are applicable to each of the 8 activity topics, were included as well.Conclusion:An intervention taxonomy is required to study the SW/CM interventions and the potential association with positive rehabilitation outcomes for patients with SCI. The SW/CM taxonomy developed for the SCIRehab project, which will be used with 1,500 patients admitted to 6 SCIRehab centers over 2.5 years, will provide an infrastructure for such research.

The fairness of quality assessment methods is under debate. Quality indicators incorporating the longitudinal nature of care have been advocated but their usefulness in comparison to more commonly used cross-sectional measures is not clear.