Early biological markers of post-acute sequelae of SARS-CoV-2 infection.

To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

Where Does Hope Lie? The Dialectical Tensions Between Hopes and Expectations of Vocational Transition Planning from the Perspectives of Autistic Young Adults, Parents, and Practitioners.

The post-secondary transition for autistic youth is a complex process, with hopes and expectations serving as malleable mediators often overlooked in research and practice. Career awareness, exploration, and counseling services play a critical role in facilitating vocational transition, but the vocational hopes and expectations of autistic youth and their parents are often disregarded. This study aims to explore these aspirations and their impact on the vocational transition process, seeking to harmonize elements to better align with the needs of autistic youth and their families. This study used a focus group design involving group interviews with three participant groups: autistic transition-aged youth, parents, and practitioners. The findings reveal five key themes: 1) Accepting Disability or Constrained by Ableism: Resisting Marginalization, 2) Finding the Sweet Spot: Are Parents and Youth's Expectations Too High or Too Low, 3) Market Forces at Work-Finding a Meaningful Vocational Path in a Capitalist Society, 4) Despite Meticulous Planning, there is a Disconnect Between Needs and Resources, and 5) The Hills and Valleys of Finding Resilience. Navigating the multifaceted landscape of vocational transition planning for autistic youth necessitates a collaborative and flexible approach. Identified tensions serve as opportunities for growth and transformation. Recognizing and addressing system shortcomings is crucial for informed decision-making. Challenges extend beyond individual circumstances, reflecting broader systemic issues, and identifying these gaps allows for a comprehensive understanding of available resources, cultivating a basis of hope as uncertainties are addressed.

Homeostatic cytokines reciprocally modulate the emergence of prenatal effector PLZF+CD4+ T cells in humans.

The development of human prenatal adaptive immunity progresses faster than previously appreciated, with the emergence of memory CD4+ T cells alongside regulatory T cells by midgestation. We previously identified a prenatal specific population of promyelocytic leukemia zinc finger-positive (PLZF+) CD4+ T cells with heightened effector potential that were enriched in the developing intestine and accumulated in the cord blood of infants exposed to prenatal inflammation. However, the signals that drive their tissue distribution and effector maturation are unknown. Here, we define the transcriptional and functional heterogeneity of human prenatal PLZF+CD4+ T cells and identify the compartmentalization of T helper-like (Th-like) effector function across the small intestine (SI) and mesenteric lymph nodes (MLNs). IL-7 was more abundant in the SI relative to the MLNs and drove the preferential expansion of naive PLZF+CD4+ T cells via enhanced STAT5 and MEK/ERK signaling. Exposure to IL-7 was sufficient to induce the acquisition of CD45RO expression and rapid effector function in a subset of PLZF+CD4+ T cells, identifying a human analog of memory phenotype CD4+ T cells. Further, IL-7 modulated the differentiation of Th1- and Th17-like PLZF+CD4+ T cells and thus likely contributes to the anatomic compartmentalization of human prenatal CD4+ T cell effector function.

Providing quality employment services to people living with asthma in the vocational rehabilitation program: A model for meeting the needs of an emerging clientele.

BACKGROUND: With incidence and prevalence rates of asthma diagnoses steadily increasing in the United States and worldwide over the past 30 years, people with asthma are an emerging vocational rehabilitation (VR) consumer population. OBJECTIVE: This article describes the job acquisition and return to work considerations facing employees with asthma. METHODS: Following an overview of the etiology, incidence, prevalence, and career development implications of this chronic respiratory disease, the authors present career preparatory and return to work recommendations to meet the needs of Americans with asthma across the phases of the VR process. RESULTS: The importance of access to quality healthcare, lifestyle, and environmental modifications to promote respiratory health, employer consultation, workplace accommodations and universal design, and interface with medical and mental health professionals is emphasized throughout the article. CONCLUSION: Asthma is an emerging disability that disproportionally affects people of color and people who live in poverty. Rehabilitation professionals must be prepared to meet the needs of this growing and diverse clientele as people with asthma seek assistance from the VR program in acquiring, maintaining, and advancing in meaningful, satisfying employment.

Bi2Se3 nanoplates for contrast-enhanced photoacoustic imaging at 1064 nm.

Photoacoustic (PA) imaging is a high-resolution biomedical imaging modality, which can be used to visualize biological tissues located beyond the limited penetration depth of existing optical imaging techniques. An optical wavelength of 1064 nm is of great interest in PA imaging due to low intrinsic absorption at this wavelength. Reduced absorption implies an increased depth of imaging, which enables several new clinical applications such as bladder imaging, gastrointestinal (GI) imaging, and sentinel lymph node (SLN) imaging. In addition, a 1064 nm Nd:YAG laser system enables a high power, cost-effective, and compact laser-based PA imaging system. However, at this wavelength, due to low intrinsic contrast, high absorption exogenous PA contrast agents are necessary for imaging. To this end, we present new Bi2Se3 nanoplates as PA contrast agents at 1064 nm wavelength for PA imaging. We successfully synthesized Bi2Se3 nanoplates and they exhibited relatively strong PA signals at 1064 nm. We confirmed the increased imaging depth of penetration by imaging the Bi2Se3-containing tube located 4.6 cm deep in biological tissues. We present in vivo PA imaging of the bladder, GI tract, and SLN in mice using a Bi2Se3 contrast agent establishing the clinical feasibility of these agents with a clinical photoacoustic/ultrasound imaging system. Our results confirm that Bi2Se3 nanoplates are promising PA contrast agents at 1064 nm that offer a high optical absorbance in the second NIR region providing a high contrast imaging and increased depth of penetration.

The impact of diet-induced hepatic steatosis in a murine model of hepatic ischemia/reperfusion injury.

The prevalence of obesity-associated nonalcoholic fatty liver disease has significantly increased over the past decade, and end-stage liver disease secondary to nonalcoholic steatohepatitis has become 1 of the most common indications for liver transplantation. This both increases the demand for organs and decreases the availability of donor livers deemed suitable for transplantation. Although in the past many steatotic livers were discarded due to concerns over enhanced susceptibility to ischemia/reperfusion injury (IRI) and organ failure, the discrepancy between supply and demand has resulted in increasing use of expanded criteria donor organs including steatotic livers. However, it remains controversial whether steatotic livers can be safely used for transplantation and how best to improve the performance of steatotic grafts. We aimed to evaluate the impact of diet-induced hepatic steatosis in a murine model of IRI. Using a diet of high trans-fat, fructose, and cholesterol (HTF-C) and a diet high in saturated fats, sucrose, and cholesterol (Western diet), we were able to establish models of mixed macrovesicular and microvesicular steatosis (HTF-C) and microvesicular steatosis (Western). We found that the presence of hepatic steatosis, whether it is predominantly macrovesicular or microvesicular, significantly worsens IRI as measured by plasma alanine aminotransferase levels and inflammatory cytokine concentration, and histological evaluation for necrosis. Additionally, we report on a novel finding in which hepatic IRI in the setting of steatosis results in the induction of the necroptosis factors, receptor interacting protein kinase (RIPK) 3, RIPK1, and mixed-lineage kinase domain-like. These data lay the groundwork for additional experimentation to test potential therapeutic approaches to limit IRI in steatotic livers by using a genetically tractable system. Liver Transplantation 24 908-921 2018 AASLD.

Adult Spinal Deformity Knowledge in Orthopedic Spine Surgeons: Impact of Fellowship Training, Experience, and Practice Characteristics.

STUDY DESIGN: Survey study. OBJECTIVE: The purpose of this paper was to assess the level of adult spine deformity (ASD) knowledge among orthopedic spine surgeons and identify areas for improvement in spine surgery training. SUMMARY OF BACKGROUND DATA: ASD is increasingly encountered in spine surgery practice. While ASD knowledge among neurosurgeons has been evaluated, ASD knowledge among orthopedic spine surgeons has not previously been reported. METHODS: A survey of orthopedic spine surgeon members of North American Spine Society (NASS) was conducted to assess level of spine surgery training, practice experience, and spinal deformity knowledge base. The survey used was previously completed by a group of neurologic surgeons with published results. The survey used 11 questions developed and agreed upon by experienced spinal deformity surgeons. RESULTS: Complete responses were received from 413 orthopedic spine surgeons. The overall correct-answer rate was 69.0%. Surgeons in practice for less than 10 years had a higher correct-answer rate compared to those who have practiced for 10 years or more (74% vs. 67%; p = .000003). Surgeons with 75% or more of their practice dedicated to spine had a higher overall correct rate compared to surgeons whose practice is less than 75% spine (71% vs. 63%; p = .000029). Completion of spine fellowship was associated with a higher overall correct-answer rate compared to respondents who did not complete a spine fellowship (71% vs. 59%; p < .00001). CONCLUSIONS: Completion of spine fellowship and having a dedicated spine surgery practice were significantly associated with improved performance on this ASD knowledge survey. Unlike neurosurgeons, orthopedic spine surgeons who have practiced for less than 10 years performed better than those who have practiced for more than 10 years. Ongoing emphasis on spine deformity education should be emphasized to improve adult spinal deformity knowledge base.

Factors predicting publication of spinal cord injury trials registered on www.ClinicalTrials. gov.

OBJECTIVE/BACKGROUND: Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. DESIGN: Retrospective analysis of publically available data on www.ClinicalTrials.gov. METHODS: The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. RESULTS: There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). CONCLUSION: The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.

Targeted exome sequencing of Korean triple-negative breast cancer reveals homozygous deletions associated with poor prognosis of adjuvant chemotherapy-treated patients.

Triple-negative breast cancer is characterized by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is associated with a poorer outcome than other subtypes of breast cancer. Moreover, there are no accurate prognostic genes or effective therapeutic targets, thereby necessitating continued intensive investigation. This study analyzed the genetic mutation landscape in 70 patients with triple-negative breast cancer by targeted exome sequencing of tumor and matched normal samples. Sequencing showed that more than 50% of these patients had deleterious mutations and homozygous deletions of DNA repair genes, such as ATM, BRCA1, BRCA2, WRN, and CHEK2. These findings suggested that a large number of patients with triple-negative breast cancer have impaired DNA repair function and that therefore a poly ADP-ribose polymerase inhibitor may be an effective drug in the treatment of this disease. Notably, homozygous deletion of three genes, EPHA5, MITF, and ACSL3, was significantly associated with an increased risk of recurrence or distant metastasis in adjuvant chemotherapy-treated patients.

Real-time Triple-modal Photoacoustic, Ultrasound, and Magnetic Resonance Fusion Imaging of Humans.

Imaging that fuses multiple modes has become a useful tool for diagnosis and therapeutic monitoring. As a next step, real-time fusion imaging has attracted interest as for a tool to guide surgery. One widespread fusion imaging technique in surgery combines real-time ultrasound (US) imaging and pre-acquired magnetic resonance (MR) imaging. However, US imaging visualizes only structural information with relatively low contrast. Here, we present a photoacoustic (PA), US, and MR fusion imaging system which integrates a clinical PA and US imaging system with an optical tracking-based navigation sub-system. Through co-registration of pre-acquired MR and real-time PA/US images, overlaid PA, US, and MR images can be concurrently displayed in real time. We successfully acquired fusion images from a phantom and a blood vessel in a human forearm. This fusion imaging can complementarily delineate the morphological and vascular structure of tissues with good contrast and sensitivity, has a well-established user interface, and can be flexibly integrated with clinical environments. As a novel fusion imaging, the proposed triple-mode imaging can provide comprehensive image guidance in real time, and can potentially assist various surgeries.

Programmable Real-time Clinical Photoacoustic and Ultrasound Imaging System.

Photoacoustic imaging has attracted interest for its capacity to capture functional spectral information with high spatial and temporal resolution in biological tissues. Several photoacoustic imaging systems have been commercialized recently, but they are variously limited by non-clinically relevant designs, immobility, single anatomical utility (e.g., breast only), or non-programmable interfaces. Here, we present a real-time clinical photoacoustic and ultrasound imaging system which consists of an FDA-approved clinical ultrasound system integrated with a portable laser. The system is completely programmable, has an intuitive user interface, and can be adapted for different applications by switching handheld imaging probes with various transducer types. The customizable photoacoustic and ultrasound imaging system is intended to meet the diverse needs of medical researchers performing both clinical and preclinical photoacoustic studies.

Restaurant Menu Labeling Policy: Review of Evidence and Controversies.

In response to high rates of obesity in the USA, several American cities, counties, and states have passed laws requiring restaurant chains to post labels identifying the energy content of items on menus, and nationwide implementation of menu labeling is expected in late 2016. In this review, we identify and summarize the results of 16 studies that have assessed the impact of real-world numeric calorie posting. We also discuss several controversies surrounding the US Food and Drug Administration's implementation of federally mandated menu labeling. Overall, the evidence regarding menu labeling is mixed, showing that labels may reduce the energy content of food purchased in some contexts, but have little effect in other contexts. However, more data on a range of ong-term consumption habits and restaurant responses is needed to fully understand the impact menu labeling laws will have on the US population's diet.

Readability of self-report alcohol misuse measures.

OBJECTIVE: Self-report measures of alcohol misuse and alcohol use disorders are valuable assessment tools for both research and clinical practice settings. However, readability is often overlooked when establishing the validity of these measures, which may result in measures written at a reading-grade level that is higher than the ability level of many potential respondents. The aim of the current study was to estimate the reading-grade level of validated measures of alcohol misuse and associated problems. METHOD: A total of 45 measures were identified, and reading-grade level was calculated using three validated readability formulas. RESULTS: The majority of measures were written above the recommended reading-grade level for patient materials (5th-6th grade), with particularly poor readability for measure instructions. CONCLUSIONS: Given that many self-report alcohol misuse measures are written at a high reading-grade level, the consideration of readability is important when selecting measures for use in research and practice settings. Moreover, the development or modification of measures to target low-literacy populations may facilitate the broader applicability of these instruments.

Cue-induced craving in dependence upon prescription opioids and heroin.

BACKGROUND AND OBJECTIVES: Cues associated with heroin use (eg, needles, powder) elicit robust craving responses in individuals dependent upon heroin. Elevated cue-induced craving may be a risk factor for relapse and can persist after periods of drug abstinence. Despite the growing prevalence of opioid dependence involving prescription opioids, published studies have yet to examine whether cue-induced craving is also present in prescription opioid dependence. METHODS: A sample of 50 adults diagnosed with opioid dependence (20 prescription opioid users, 25 heroin users, and 5 mixed opioid users) completed a cue reactivity assessment. Participants were administered a series of 90 pictures, including heroin-specific, prescription opioid-specific, and neutral images, and were asked to rate craving and cue salience after each image. RESULTS: Both the prescription opioid and heroin groups experienced significantly more craving to drug than to neutral stimuli. The prescription opioid group reported significantly less craving to prescription opioid stimuli than the heroin group to heroin stimuli; however, this effect was smaller and non-significant when controlling for group differences in cue salience. DISCUSSION AND CONCLUSIONS: This study found evidence for cue-induced craving in individuals dependent upon prescription opioids. Further research is needed to better understand the role of cue reactivity in the course and treatment of opioid dependence involving prescription opioid use. SCIENTIFIC SIGNIFICANCE: As elevated craving reactivity to drug cues may reflect a risk factor for relapse, understanding the nature of cue-induced craving in individuals with opioid dependence is important to improving treatments for this population.

Reliability and accuracy of intradermal injection by Mantoux technique, hypodermic needle adapter, and hollow microneedle in pigs.

We compared the ability of three intradermal delivery devices to administer an intended dose to pig skin in vivo and target that dose to the dermal rather than subcutaneous layers. The three devices were a standard hypodermic needle and syringe for the Mantoux technique, an adapter designed to facilitate proper hypodermic needle and syringe use, and a hollow microneedle. Reliability was determined as the percentage of the administered dose that entered the skin, as opposed to remaining in the device or on the skin surface. The intradermal adapter (97.6 ± 1.5 % delivered, mean ± standard deviation), Mantoux technique (95.4 ± 4.9 %), and hollow microneedle (94.9 ± 0.3 %) exhibited similar reliability. Accuracy was determined as the percentage of the dose that entered the skin that localized in the dermis. All three devices achieved similar accuracy: hollow microneedle (99 ± 12 % delivered to the dermis, median ± standard deviation), Mantoux technique (97 ± 16 %), and intradermal adapter (92 ± 21 %). We conclude that intradermal injection by all three methods studied provided reliable delivery to the skin and provided accurate localization of delivery within the dermis. Next-generation designs of these devices have now received clearance from the FDA and are used as medical products and/or in clinical trials.

ES cell-derived renewable and functional midbrain dopaminergic progenitors.

During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2(+)Corin(+) cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2(+)Corin(+) cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2(+)Corin(+) cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening.

Clinicopathologic features and treatment outcomes in malignant lymphoma of pediatric and young adult patients in Korea: comparison of korean all-ages group and Western younger age group.

PURPOSE: The aim of this study is to define distinctive clinicopathologic features of malignant lymphoma in pediatric and young adult patients, particularly in Korea. PATIENTS AND METHODS: From May 1993 to November 2005, 294 pediatric and young adult patients (age range, 0-31 years) with malignant lymphoma were analyzed in this study at Samsung Medical Center. We also compared this group with the Korean all-ages group and Western younger age group using previously reported data. RESULTS: Hodgkin disease appears more common in the younger age group than in the all-ages group (15% vs. 5.3%; P = .001). Among patients with non-Hodgkin lymphoma (NHL), T/natural killer cell immunophenotype is more common in the present younger age group than the all-ages group (45.5% vs. 25%; P = .001) and Western younger age group (45.5% vs. 13.3%; P = .001). Lymphoblastic lymphoma and T-anaplastic large-cell lymphoma included relatively higher proportions in the younger age group. Overall survival for patients in the group aged 21-31 years was significantly inferior to that of the other younger age group (P = .014). CONCLUSION: The incidence of Hodgkin disease and T-cell NHL is relatively higher in pediatric and young-adult population group than the all-ages group. However, treatment outcome of the younger age group, excluding lymphoblastic lymphoma, seems to be similar to those in any age group.