A comprehensive transcriptional map of primate brain development.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.

Evaluating Quality of "Medical Tourism" For Heart Surgery: Measures That Matter.

There are some success stories. Lowe's pioneering flat-rate deal with the Cleveland Clinic for heart surgery has shown both cost savings and quality improvement. Other large employers, notably Walmart and PepsiCo, have followed suit, signing contracts with self-described, single-hospital "centers of excellence" for a handful of elective procedures.

Behavioral Engagement and Activation Model Study (BEAMS): A latent class analysis of adopters and non-adopters of digital health technologies among people with Type 2 diabetes.

Many people with Type 2 diabetes (T2D) who could benefit from digital health technologies (DHTs) are either not using DHTs or do use them, but not for long enough to reach their behavioral or metabolic goals. We aimed to identify subgroups within DHT adopters and non-adopters and describe their unique profiles to better understand the type of tailored support needed to promote effective and sustained DHT use across a diverse T2D population. We conducted latent class analysis of a sample of adults with T2D who responded to an internet survey between December 2021 and March 2022. We describe the clinical and psychological characteristics of DHT adopters and non-adopters, and their attitudes toward DHTs. A total of 633 individuals were characterized as either DHT "Adopters" (n = 376 reporting any use of DHT) or "Non-Adopters" (n = 257 reporting never using any DHT). Within Adopters, three subgroups were identified: 21% (79/376) were "Self-managing Adopters," who reported high health activation and self-efficacy for diabetes management, 42% (158/376) were "Activated Adopters with dropout risk," and 37% (139/376) were "Non-Activated Adopters with dropout risk." The latter two subgroups reported barriers to using DHTs and lower rates of intended future use. Within Non-Adopters, two subgroups were identified: 31% (79/257) were "Activated Non-Adopters," and 69% (178/257) were "Non-Adopters with barriers," and were similarly distinguished by health activation and barriers to using DHTs. Beyond demographic characteristics, psychological, and clinical factors may help identify different subgroups of Adopters and Non-Adopters.

In this study, we characterized subgroups of adopters and non-adopters of digital health technologies (DHTs) for managing Type 2 diabetes, such as apps to track nutrition, continuous glucose monitors, and activity monitors like Fitbit. Self-efficacy for diabetes management, health activation, and perceived barriers to use DHT emerged as characteristics that distinguished subgroups. Notably, subgroups of adopters differed in their interest to use these technologies in the next 3 months; groups with low levels of self-efficacy and health activation were least interested in using them and thus at risk of discontinuing use. The ability to identify these subgroups can inform strategies tailored to each subgroup that motivate adoption of DHTs and promote long-term engagement.

Knowledge, attitude, and practice assessment toward COVID-19 among communities in East Nusa Tenggara, Indonesia: A cross-sectional study.

Objective: This research aimed to assess the knowledge, attitude and practice toward COVID-19 among East Nusa Tenggara (NTT) population and identify associated sociodemographic factors. Methods: A cross-sectional study was performed among communities in 22 regencies of NTT between October-November 2021 using a structured and validated questionnaire that consists of 22-items of knowledge, 6-items of attitude and 13-items of practice related COVID-19 questions. A cut off point of at least 70% was employed to categorize good knowledge, attitude, and practice. Results: The percentages of survey respondents showing good knowledge, attitude and practice toward COVID-19 were 79.8, 72.7, and 94.6%, respectively. There was a significant positive, though weak, linear correlation between knowledge and practice scores (ρ = 0.097; p = 0.049). Knowledge was strongly associated with regency of residence (Cramer's V = 0.266; p = 0.010), education (Cramer's V = 0.312; p < 0.001), and occupation (Cramer's V = 0.313; p < 0.001). Attitude and practice had strong relationship with regency of residence (Cramer's V = 0.289; p = 0.024) and education (Cramer's V = 0.272; p < 0.001), respectively. Conclusion: Nearly all survey participants showed good precautionary behaviors, but there was still a quarter of respondents indicated poor knowledge and attitude. There was also a positive relationship between knowledge and practice scores thereby indicating the importance of local public health advocates to distribute information uniformly especially to the groups with inadequate knowledge toward COVID-19 as a means to control the virus transmission.

3D-printed nails for aesthetic silicone prostheses.

BACKGROUND AND AIM: The nail is a crucially important part that needs to be closely reproduced in aesthetic silicone prostheses. The traditional method of producing prosthetic nails is a laborious process often fraught with errors and rejects. In this article, additive manufacturing or 3D printing intervention was sought to make this process less time-consuming and more exacting. STUDY DESIGN AND TECHNIQUE: With a focus on finger prosthesis, the process involves reverse engineering a patient's hand using a 3D scanner to obtain a digital blue print for referencing. 3D models of the nail shapes were created using CAD software. Colors sampling is obtained using image processing software from 2D digital images. Using specifically the inkjet technology from Stratasys, batches of nails of different sizes and colors were printed, which were then used for manual adhesion to silicone finger prostheses. RESULTS AND CONCLUSIONS: This article has demonstrated that 3D printing is able to produce nails of comparable quality with those produced by traditional methods in size, shape, curvature, and thickness. More consistent thickness, better size, and shape-matching using 3D files also minimize rejects and grinding time when finishing a prosthesis, leading to significant time savings. However, 3D-printed nails fall short in color match, surface texture, and life-likeness. Traditionally produced nails that are made using a more translucent grade of acrylic than that used in the 3D-printed nails are better able to reproduce the life-like coloration of the translucent human nail. The limitations encountered with 3D printing as applied to prosthetic nails production relate to camera settings, digital image color capture and display, differences in color system used in the printer and monitor, ambient lighting, and suitability of acrylic grade used with the proprietary 3D printing system for material translucency or opacity.

Different clinical symptom patterns in patients with reflux micro-aspiration.

BACKGROUND: Pulmonary manifestation of gastro-oesophageal reflux disease (GORD) is a well-recognised entity; however, little primary reported data exists on presenting symptoms of patients in whom reflux micro-aspiration is confirmed. The aim of this study is to report symptoms and presenting patterns of a large group of patients with confirmed reflux micro-aspiration. PATIENTS AND METHODS: Data was extracted from a prospectively populated database of patients referred to a tertiary specialist centre with severe, refractory or atypical reflux. Patients with reflux micro-aspiration on scintigraphy were included in this study. A separate group included patients with evidence of proximal reflux to the level of pharynx when supine and/or upright. RESULTS: Inclusion criteria were met by 243 patients with confirmed reflux micro-aspiration (33% males; mean age 59). Most common symptoms amongst patients with micro-aspiration were regurgitation (72%), cough (67%), heartburn (66%), throat clearing (65%) and dysphonia (53%). The most common two-symptom combinations were heartburn/regurgitation, cough/throat clearing, regurgitation/throat clearing, cough/regurgitation and dysphonia/throat clearing. The most common three-symptom combinations were cough/heartburn/regurgitation, cough/regurgitation/throat clearing and dysphonia/regurgitation/throat clearing. Cluster analysis demonstrated two main symptom groupings, one suggestive of proximal volume reflux symptoms and the other with motility/inflammatory bowel syndrome-like symptoms (bloat, constipation). CONCLUSION: The combination of typical symptoms of GORD such as heartburn or regurgitation and a respiratory or upper aero-digestive complaint such as cough, throat clearing or voice change should prompt consideration of reflux micro-aspiration.

Cellular resolution anatomical and molecular atlases for prenatal human brains.

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at postconceptional weeks (PCW) 15 and 21. Both atlases were annotated on sequential Nissl-stained sections covering brain-wide structures on the basis of combined analysis of cytoarchitecture, acetylcholinesterase staining, and an extensive marker gene expression dataset. This high information content dataset allowed reliable and accurate demarcation of developing cortical and subcortical structures and their subdivisions. Furthermore, using the anatomical atlases as a guide, spatial expression of 37 and 5 genes from the brains, respectively, at PCW 15 and 21 was annotated, illustrating reliable marker genes for many developing brain structures. Finally, the present study uncovered several novel developmental features, such as the lack of an outer subventricular zone in the hippocampal formation and entorhinal cortex, and the apparent extension of both cortical (excitatory) and subcortical (inhibitory) progenitors into the prenatal olfactory bulb. These comprehensive atlases provide useful tools for visualization, segmentation, targeting, imaging, and interpretation of brain structures of prenatal human brain, and for guiding and interpreting the next generation of cell census and connectome studies.

Vitreoretinal abnormalities in corona virus disease 2019 patients: What we know so far.

The coronavirus disease 2019 (COVID-19) has become a global pandemic since December 2019. Although COVID-19 primarily affects the respiratory systems, it has become abundantly clear that it involves multiple organs including the heart, kidney, skin, and brain. Neuro-ophthalmic signs and anterior segment inflammation of the eyes were documented in COVID-19 patients recently. Small but growing number of literatures has also reported the cases of new onset vitreoretinal disorders related to COVID-19 infection. A comprehensive search from four online databases was done. Findings show vitreoretinal involvement in COVID-19 patients including the central retinal vein occlusion, central retinal artery occlusion, reactivation of previous uveitis, chorioretinitis, macular hemorrhage, acute macular neuroretinopathy, paracentral acute middle maculopathy, vitritis with outer retinal abnormalities, varicella zoster virus-related acute retinal necrosis in immunocompromised patient, and other posterior segment pathological changes. The hypotheses for potential pathogenesis of these manifestations are direct viral ocular infection and thromboembolic complications secondary to the hyperinflammatory response. This is the first review article, which provides an overview of current evidence regarding the vitreoretinal manifestations in COVID-19 patients.

Does composite repair of giant paraoesophageal hernia improve patient outcomes?

BACKGROUND: Paraoesophageal hernia (PEH) is often symptomatic and reduces patients' quality of life (QoL). There is ongoing debate regarding the most effective surgical technique to repair giant PEH. This study aimed to see if an elective laparoscopic non-mesh composite technique of giant PEH repair offered an advantage in symptom control, hernia recurrence, QoL, morbidity and mortality. METHODS: Data were extracted from a prospectively maintained database of patients undergoing hiatal hernia repair. Composite hernia repairs from inception for giant PEH between March 2009 and December 2015 were included. Perioperative mortality, complications, hernia recurrence rates, prevalence, recurrence of symptoms and QoL were included in analysis. RESULTS: Inclusion criteria were met by 218 patients. Mean age was 70 (49-93). The average hernia size was 62% (range 30-100%; SD 21). There was one perioperative death and three significant complications (Clavien-Dindo grade III and IV). Recurrence rate was 24.8%. Without recurrence, QoL improved significantly across all domains. Recurrence of hiatus hernia reduced QoL. Surgery resulted in resolution of symptoms other than dysphagia which was incompletely improved. Patients' overall satisfaction with surgery was high. CONCLUSION: Composite repair of giant PEH is safe with overall good outcomes. Majority of hernia recurrence are small and asymptomatic. Hernia recurrence negatively affected long-term QoL scores.

A single-group pretest posttest design using full kinetic chain manipulative therapy with rehabilitation in the treatment of 18 patients with hip osteoarthritis.

OBJECTIVE: Hip osteoarthritis (HOA) affects 30 million Americans or more, and is a leading cause of disability, suffering, and pain. Standard treatments are minimally effective and carry significant risk and expense. This study assessed treatment effects of a chiropractic protocol for HOA. METHODS: Eighteen individuals, who did not qualify due to low baseline Western Ontario and McMaster Osteoarthritis Index scores (WOMAC) for other ongoing HOA randomized control trials, were selected. A prospectively planned protocol, consisting of axial manipulation to the affected hip with modified Thomas and active assisted stretch, was combined with full kinetic chain treatment or manipulative therapy to the spine, knee, ankle, or foot and assessed with use of valid and reliable outcome measures. RESULTS: The primary outcome measure, the Overall Therapy Effectiveness Tool, was assessed with chi(2) and demonstrated that 83.33% of participants were improved after the ninth visit, P = .005, and 78% improved at the 3-month follow-up, P = .018. Using the paired t test, WOMAC was improved 64% at the ninth visit, P = .000, and 47% at follow-up, P = .016. CONCLUSION: In HOA patients with lower WOMAC scores, a highly organized HOA treatment appears to have resulted in statistically and clinically meaningful intragroup changes in the Overall Effectiveness Therapy Tool, WOMAC, Harris Hip Scale, and range of motion, all with P

Fistulae involving the appendix: a systematic review of the literature.

BACKGROUND: The appendix has a unique place in surgical history. Although the first ever appendicectomy involved a fistula to the skin, fistulae involving the appendix remain uncommon and can lead to unique surgical considerations. METHODS: A systematic review of the literature was performed for case reports of appendiceal fistulae. We excluded cases in which the patient had a history of appendicectomy. Cases were categorized by site and aetiology, with information regarding relative frequency and demographics obtained. RESULTS: A total of 301 case reports of fistula involving the appendix were found. The most common sites of these fistulae were to the bladder (148 cases), skin (40 cases), vasculature (19 cases), umbilicus (16 cases) and to the gastrointestinal tract. The most common aetiology in sub-analysis was appendicitis alone (150 cases), with less common causes including appendiceal adenocarcinoma (32 cases) and congenital abnormalities (18 cases). There were significantly more appendiceal fistulae in males than in females, with a ratio of 1.7:1. In patients with appendiceal adenocarcinoma as a cause for fistula, there were significantly more females than males with a ratio of 2.3:1. CONCLUSION: In conducting a systematic review of case reports of fistulae involving the appendix, we identified 301 unique case reports, with a range of different sites and aetiologies.

A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex.

To understand how the brain processes sensory information to guide behavior, we must know how stimulus representations are transformed throughout the visual cortex. Here we report an open, large-scale physiological survey of activity in the awake mouse visual cortex: the Allen Brain Observatory Visual Coding dataset. This publicly available dataset includes the cortical activity of nearly 60,000 neurons from six visual areas, four layers, and 12 transgenic mouse lines in a total of 243 adult mice, in response to a systematic set of visual stimuli. We classify neurons on the basis of joint reliabilities to multiple stimuli and validate this functional classification with models of visual responses. While most classes are characterized by responses to specific subsets of the stimuli, the largest class is not reliably responsive to any of the stimuli and becomes progressively larger in higher visual areas. These classes reveal a functional organization wherein putative dorsal areas show specialization for visual motion signals.

A feasibility study comparing two chiropractic protocols in the treatment of patellofemoral pain syndrome.

OBJECTIVE: The purpose of this pilot study was to determine the feasibility of (1) using the existing clinic, clinicians, interns, faculty, and staff from our college in conducting all components of a planned randomized controlled clinical trial; (2) successfully recruiting patients with patellofemoral pain syndrome (PFPS); and (3) consistently, effectively, and safely implementing the study protocols and therapy. METHODS: Diagnostic, treatment, and blind assessment procedures were carried out while recruitment and administrative techniques for managing long-term storage of data and files were developed. Thirty-one patients were randomized into a local manipulative group (group A) or to a full kinetic chain manipulative therapy group (group B), each combined with exercise and soft tissue treatment. The Anterior Knee Pain Scale, visual analog scale, and Patient Satisfaction Scale were used. RESULTS: All phases of the feasibility study including use of the clinic, staff, recruitment techniques, treatment protocols, data collection, input, and analysis were effectively and safely carried out. CONCLUSIONS: A feasibility study investigating the ability to conduct a randomized controlled trial of a manipulative therapy protocol for PFPS using available chiropractic college infrastructure was accomplished. A fully powered PFPS trial is feasible and merited.

t-PA Suppresses the Immune Response and Aggravates Neurological Deficit in a Murine Model of Ischemic Stroke.

Introduction: Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. While thrombolytic therapy with tissue-type plasminogen activator (t-PA) is still the only pharmacological treatment for AIS, plasmin, the effector protease, has been reported to suppress dendritic cells (DCs), known for their potent antigen-presenting capacity. Accordingly, in the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion. To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke. Methods: C57Bl/6J wild-type mice and plasminogen-deficient (plg-/-) mice were subjected to middle cerebral artery occlusion (MCAo) for 60 min followed by mouse t-PA treatment (0.9 mg/kg) at reperfusion. Behavioral testing was performed 23 h after occlusion, pursued by determination of blood counts and plasma cytokines at 24 h. Spleens and cervical lymph nodes (cLN) were also harvested and characterized by flow cytometry. Results: MCAo resulted in profound attenuation of immune activation, as anticipated. t-PA treatment not only worsened neurological deficit, but further reduced lymphocyte and monocyte counts in blood, enhanced plasma levels of both IL-10 and TNFα and decreased various conventional DC subsets in the spleen and cLN, consistent with enhanced immunosuppression and systemic inflammation after stroke. Many of these effects were abolished in plg-/- mice, suggesting plasmin as a key mediator of t-PA-induced immunosuppression. Conclusion: t-PA, via plasmin generation, may weaken the immune response post-stroke, potentially enhancing infection risk and impairing neurological recovery. Due to the large number of comparisons performed in this study, additional pre-clinical work is required to confirm these significant possibilities. Future studies will also need to ascertain the functional implications of t-PA-mediated immunosuppression for thrombolyzed AIS patients, particularly for those with failed recanalization.

An anatomic transcriptional atlas of human glioblastoma.

Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.

Insulin regulation of skeletal muscle PDK4 mRNA expression is impaired in acute insulin-resistant states.

We previously showed that insulin has a profound effect to suppress pyruvate dehydrogenase kinase (PDK) 4 expression in rat skeletal muscle. In the present study, we examined whether insulin's effect on PDK4 expression is impaired in acute insulin-resistant states and, if so, whether this change is accompanied by decreased insulin's effects to stimulate Akt and forkhead box class O (FOXO) 1 phosphorylation. To induce insulin resistance, conscious overnight-fasted rats received a constant infusion of Intralipid or lactate for 5 h, while a control group received saline infusion. Following the initial infusions, each group received saline or insulin infusion (n = 6 or 7 each) for an additional 5 h, while saline, Intralipid, or lactate infusion was continued. Plasma glucose was clamped at basal levels during the insulin infusion. Compared with the control group, Intralipid and lactate infusions decreased glucose infusion rates required to clamp plasma glucose by approximately 60% (P < 0.01), confirming the induction of insulin resistance. Insulin's ability to suppress PDK4 mRNA level was impaired in skeletal muscle with Intralipid and lactate infusions, resulting in two- to threefold higher PDK4 mRNA levels with insulin (P < 0.05). Insulin stimulation of Akt and FOXO1 phosphorylation was also significantly decreased with Intralipid and lactate infusions. These data suggest that insulin's effect to suppress PDK4 gene expression in skeletal muscle is impaired in insulin-resistant states, and this may be due to impaired insulin signaling for stimulation of Akt and FOXO1 phosphorylation. Impaired insulin's effect to suppress PDK4 expression may explain the association between PDK4 overexpression and insulin resistance in skeletal muscle.

Brain-computer communication: motivation, aim, and impact of exploring a virtual apartment.

The step away from a synchronized or cue-based brain-computer interface (BCI) and from laboratory conditions towards real world applications is very important and crucial in BCI research. This work shows that ten naive subjects can be trained in a synchronous paradigm within three sessions to navigate freely through a virtual apartment, whereby at every junction the subjects could decide by their own, how they wanted to explore the virtual environment (VE). This virtual apartment was designed similar to a real world application, with a goal-oriented task, a high mental workload, and a variable decision period for the subject. All subjects were able to perform long and stable motor imagery over a minimum time of 2 s. Using only three electroencephalogram (EEG) channels to analyze these imaginations, we were able to convert them into navigation commands. Additionally, it could be demonstrated that motivation is a very crucial factor in BCI research; motivated subjects perform much better than unmotivated ones.

A review of principles in design and usability testing of tactile technology for individuals with visual impairments.

To lay the groundwork for devising, improving, and implementing new technologies to meet the needs of individuals with visual impairments, a systematic literature review was conducted to: a) describe hardware platforms used in assistive devices, b) identify their various applications, and c) summarize practices in user testing conducted with these devices. A search in relevant EBSCO databases for articles published between 1980 and 2014 with terminology related to visual impairment, technology, and tactile sensory adaptation yielded 62 articles that met the inclusion criteria for final review. It was found that while earlier hardware development focused on pin matrices, the emphasis then shifted toward force feedback haptics and accessible touch screens. The inclusion of interactive and multimodal features has become increasingly prevalent. The quantity and consistency of research on navigation, education, and computer accessibility suggest that these are pertinent areas of need for the visually impaired community. Methodologies for usability testing ranged from case studies to larger cross-sectional studies. Many studies used blindfolded sighted users to draw conclusions about design principles and usability. Altogether, the findings presented in this review provide insight on effective design strategies and user testing methodologies for future research on assistive technology for individuals with visual impairments.

Neuropathological and transcriptomic characteristics of the aged brain.

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer's disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.