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El Museo Escolar de Puçol (Elche) surgió en la década de los 70 como resultado de una experiencia educativa desarrollada en la escuela de la pedanía ilicitana homónima. En torno al conocimiento del medio se estructuró una educación que, en íntima conexión con la comunidad, patrimonializó la vida tradicional de esta partida rural. Desde sus orígenes, el voluntariado ha representado un elemento crucial en el devenir de la institución, que en 2009 fue incluida en el Registro de Buenas Prácticas de Salvaguarda del Patrimonio Cultural Inmaterial de la Humanidad de la Unesco. Palabras clave: Museo Escolar, patrimonio, comunidad, voluntariado, educación, Unesco

Context: Influenza infection results in substantial costs, morbidity, and mortality. Vaccination against influenza is particularly important in children and adolescents who are a significant source of transmission to other high-risk populations, yet pediatric and adolescent vaccine coverage remains low. Traditional vaccine reminders have had a limited effect on low-income populations; however, text messaging is a novel, scalable approach to promote influenza vaccination.Objective: To evaluate targeted text message reminders for low-income, urban parents to promote receipt of influenza vaccination among children and adolescents.Design, Setting, and Participants: Randomized controlled trial of 9213 children and adolescents aged 6 months to 18 years receiving care at 4 community-based clinics in the United States during the 2010-2011 influenza season. Of the 9213 children and adolescents, 7574 had not received influenza vaccine prior to the intervention start date and were included in the primary analysis.Intervention: Parents of children assigned to the intervention received up to 5 weekly immunization registry-linked text messages providing educational information and instructions regarding Saturday clinics. Both the intervention and usual care groups received the usual care, an automated telephone reminder, and access to informational flyers posted at the study sites.Main Outcome Measures: Receipt of an influenza vaccine dose recorded in the immunization registry via an electronic health record by March 31, 2011. Receipt was secondarily assessed at an earlier fall review date prior to typical widespread influenza activity.Results: Study children and adolescents were primarily minority, 88% were publicly insured, and 58% were from Spanish-speaking families. As of March 31, 2011, a higher proportion of children and adolescents in the intervention group (43.6%; n = 1653) compared with the usual care group (39.9%; n = 1509) had received influenza vaccine (difference, 3.7% [95% CI, 1.5%-5.9%]; relative rate ratio [RRR], 1.09 [95% CI, 1.04-1.15]; P = .001). At the fall review date, 27.1% (n = 1026) of the intervention group compared with 22.8% (n = 864) of the usual care group had received influenza vaccine (difference, 4.3% [95% CI, 2.3%-6.3%]; RRR, 1.19 [95% CI, 1.10-1.28]; P < .001).Conclusions: Among children and adolescents in a low-income, urban population, a text messaging intervention compared with usual care was associated with an increased rate of influenza vaccination. However, the overall influenza vaccination rate remained low.Trial Registration: clinicaltrials.gov Identifier: NCT01146912. [ABSTRACT FROM AUTHOR]

Numerous state systems and local mental health and vocational rehabilitation programs are currently attempting to implement supported employment. This cross-sectional survey of 26 mental health agencies, partnering with federal-state vocational rehabilitation, identified differences in access to supported employment services and rates of competitive employment (efficiency) as well as predictors of access and efficiency. Access varied from 2 to 100% and was related to the percentage of supported employment specialists per consumers with serious mental illness served by the mental health agency (funding). Efficiency varied from 7 to 75% and was related to implementation of the critical components of evidence-based supported employment and to the local unemployment rate. To help mental health clients achieve their employment goals, state systems and local programs should address consolidation of resources in supported employment and the quality of implementation of supported employment. [ABSTRACT FROM AUTHOR]

This column describes a private-public-academic collaboration in six states and the District of Columbia designed to provide evidence-based supported employment for persons with psychiatric disabilities by using best practices for program implementation. Dissemination strategies included collaborative state-level administrative oversight, longitudinal training based on established fidelity criteria, outcome-based supervision, problem solving by local experts, and selection of intervention sites on the basis of their motivation to participate. The number of clients served at participating sites increased steadily over 11 quarters, and the proportion of clients competitively employed stayed consistently over 40 percent. The project successfully combined industry's emphasis on outcomes with academia's emphasis on research-based interventions to enhance public services. [ABSTRACT FROM AUTHOR]

Cis -acting regulatory enhancer elements are valuable tools for gaining cell type-specific genetic access. Leveraging large chromatin accessibility atlases, putative enhancer sequences can be identified and deployed in adeno-associated virus (AAV) delivery platforms. However, a significant bottleneck in enhancer AAV discovery is charting their detailed expression patterns in vivo , a process that currently requires gold-standard one-by-one testing. Here we present a barcoded multiplex strategy for screening enhancer AAVs at cell type resolution using single cell RNA sequencing and taxonomy mapping. We executed a proof-of-concept study using a small pool of validated enhancer AAVs expressing in a variety of neuronal and non-neuronal cell types across the mouse brain. Unexpectedly, we encountered substantial technical and biological noise including chimeric packaging products, necessitating development of novel techniques to accurately deconvolve enhancer expression patterns. These results underscore the need for improved methods to mitigate noise and highlight the complexity of enhancer AAV biology in vivo .

Colonic melanoma is a rarely detected aetiology of small bowel obstruction. This is a case of a male in his 80s with a history of treated stage IIIA melanoma on his trunk 7 years prior who presented with small bowel obstruction. He underwent urgent surgical intervention, where a partial colectomy was performed. Pathology revealed a 4.6 cm melanoma causing intussusception. This case highlights the insidious nature of metastatic melanomas and discusses an uncommon location of melanoma metastasis that evaded detection until a late stage., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Basophil activation test (BAT) might be an alternative to nasal allergen challenge (NAC) to identify the allergic etiology in rhinitis patients. Here, we investigate the diagnostic performance of BAT for allergic phenotypes of rhinitis., Methods: Rhinitis patients and healthy controls were subjected to NAC with Dermatophagoides pteronyssinus (DP), Alternaria alternata (AA), grass (GP) and olive (OP) pollens. Rhinitis subjects also underwent skin prick test (SPT) with relevant allergens. Patients were classified into allergic rhinitis (AR, positive NAC and SPT), local allergic rhinitis (LAR, positive NAC and negative SPT), dual allergic rhinitis (DAR, defined as AR for ≥1 allergen and LAR for ≥1 allergen), and non-allergic rhinitis (NAR, negative NAC and SPT) phenotypes. BAT with DP, AA, GP and OP was conducted in study individuals and compared with NAC results., Results: A total of 47 AR, 31 DAR, 26 LAR, 12 NAR and 21 control subjects were recruited. The best positivity cut-offs of BAT for DP-, AA-, GP- and OP-driven allergy (all phenotypes) were a %CD63 cells of 8.650, 14.250, 26.200, and 12.780, respectively (AUC 0.851, 0.701, 0.887, and 0.921, respectively). Sensitivity, specificity, negative and positive predictive values of BAT (all phenotypes) ranged 43.5%(AA)-83.3%(OP), 88.9%(GP)-100%(AA), 87%(GP)-100%(AA), and 61.1%(DP)-80.0%(pollens), respectively. BAT identified 79%-100% of SPT-positive allergies (AR and DAR), and 25%-75% of SPT-negative allergies (LAR and DAR), while ≤10% of NAR/HC subjects tested positive. BAT positivity correlated with rhinitis severity in LAR patients (p = 0.018), and associated with conjunctivitis (p = 0.015) in allergic subjects., Conclusion: BAT can replace NAC for AR confirmation, and limit the number of NAC required for LAR and DAR diagnosis. BAT can demonstrate sIgE in SPT-negative allergies., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model., Competing Interests: Declaration of interests Authors JTT, BPL, EL, TLD, BTa, HZ, JKM are co-inventors on patent application PCT/US2021/45995 Artificial expression constructs for selectively modulating gene expression in striatal neurons. Authors JTT, BPL, TLD, BTa, TEB are co-inventors on provisional patent application US 63/582,759 Artificial expression constructs for modulating gene expression in the basal ganglia. HZ – is on the Scientific Advisory Board of MapLight Therapeutics, Palo Alto, CA

The mammalian cortex is comprised of cells classified into types according to shared properties. Defining the contribution of each cell type to the processes guided by the cortex is essential for understanding its function in health and disease. We used transcriptomic and epigenomic cortical cell type taxonomies from mouse and human to define marker genes and putative enhancers and created a large toolkit of transgenic lines and enhancer AAVs for selective targeting of cortical cell populations. We report evaluation of fifteen new transgenic driver lines, two new reporter lines, and >800 different enhancer AAVs covering most subclasses of cortical cells. The tools reported here as well as the scaled process of tool creation and modification enable diverse experimental strategies towards understanding mammalian cortex and brain function.

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

Dravet syndrome (DS) is a devastating developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10-20% rate of premature death. Most DS patients harbor loss-of-function mutations in one copy of SCN1A , which has been associated with inhibitory neuron dysfunction. Here we developed an interneuron-targeting AAV human SCN1A gene replacement therapy using cell class-specific enhancers. We generated a split-intein fusion form of SCN1A to circumvent AAV packaging limitations and deliver SCN1A via a dual vector approach using cell class-specific enhancers. These constructs produced full-length Na V 1.1 protein and functional sodium channels in HEK293 cells and in brain cells in vivo . After packaging these vectors into enhancer-AAVs and administering to mice, immunohistochemical analyses showed telencephalic GABAergic interneuron-specific and dose-dependent transgene biodistribution. These vectors conferred strong dose-dependent protection against postnatal mortality and seizures in two DS mouse models carrying independent loss-of-function alleles of Scn1a, at two independent research sites, supporting the robustness of this approach. No mortality or toxicity was observed in wild-type mice injected with single vectors expressing either the N-terminal or C-terminal halves of SCN1A , or the dual vector system targeting interneurons. In contrast, nonselective neuronal targeting of SCN1A conferred less rescue against mortality and presented substantial preweaning lethality. These findings demonstrate proof-of-concept that interneuron-specific AAV-mediated SCN1A gene replacement is sufficient for significant rescue in DS mouse models and suggest it could be an effective therapeutic approach for patients with DS.

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

Introduction: The global COVID-19 pandemic highlighted the importance of protecting frontline healthcare workers from novel respiratory infections while also exposing the limited instruction that medical students receive on proper donning of personal protective equipment (PPE) and more importantly the safe doffing of contaminated PPE to minimize their risk of nosocomial infection. The best methods of providing this kind of instruction have not yet been determined., Methods: Anesthesiology interns and CA-1 residents were trained on proper PPE donning and doffing for AGPs using a methodology based on Miller's pyramid and following a "knows-knows how-shows-does" progression. Participants donned PPE without instruction and were sprayed with Glo Germ® to identify areas of contamination, after which they received both video and in-person instruction on best practices for donning and doffing PPE for AGPs. Following instruction, they again donned PPE and were sprayed with Glo Germ® to identify areas of contamination., Results: 54 participants completed the study. Before training, overall donning compliance was 60% and overall doffing compliance was 48%. Overall, 70% were contaminated after PPE doffing, with 46% having multiple sites of contamination. After training, donning compliance increased by nearly 30% (P < 0.001), doffing compliance increased by over 20% (P < 0.001), and overall contamination decreased by nearly 30% (P = 0.029), with multiple-site contamination decreasing to only 6% (P = 0.013)., Discussion: While best methods for providing instruction regarding topics such as PPE donning and doffing have not yet been determined, we have demonstrated that the underlying knowledge base from medical school regarding proper donning and doffing for respiratory isolation is insufficient for preventing self-contamination, and that Miller's pyramid-based training using both video and in-person instruction combined with task execution by learners can improve compliance with PPE donning and doffing protocols and more importantly decrease skin contamination among a group of early training anesthesiology residents., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While the COVID-19 pandemic continues to strain the healthcare system, it has also expanded telemedicine. There is a subset of hospitalized moderate to severe COVID-19 patients requiring oxygen but no other intervention. This is a retrospective study of patients ≥18 years with moderate to severe COVID-19 that participated in a home monitoring program with supplemental oxygen (HMP-O 2 ) ( N  = 25). For study outcomes, HMP-O 2 participants were compared to patients meeting the same inclusion criteria but did not participate in the program ( N  = 60). On average, the HMP-O 2 patients spent 5.8 days (±5.5 days) in the hospital compared to 8.12 days (±5.5 days) for non-program patients. This resulted in 19% cost-savings for HMP-O 2 patients. Lessons learned from this program can be applied to future HMPs for either COVID-19 or other conditions that would benefit from telecare.

A metabolite of ammonium assimilation was previously theorized to be involved in the coordination of the overall nitrate response in plants. Here we show that 2-hydroxy-5-oxoproline, made by transamination of glutamine, the first product of ammonium assimilation, may be involved in signaling a plant's ammonium assimilation status. In leaves, 2-hydroxy-5-oxoproline met four foundational requirements to be such a signal. First, when it was applied to foliage, enzyme activities of nitrate reduction and ammonium assimilation increased; the activities of key tricarboxylic acid cycle-associated enzymes that help to supply carbon skeletons for amino acid synthesis also increased. Second, its leaf pools increased as nitrate availability increased. Third, the pool size of its precursor, Gln, reflected ammonium assimilation rather than photorespiration. Fourth, it was widely conserved among monocots, dicots, legumes, and nonlegumes and in plants with C3 or C4 metabolism. Made directly from the first product of ammonium assimilation, 2-hydroxy-5-oxoproline acted as a nitrate uptake stimulant. When 2-hydroxy-5-oxoproline was provided to roots, the plant's nitrate uptake rate approximately doubled. Plants exogenously provided with 2-hydroxy-5-oxoproline to either roots or leaves accumulated greater biomass. A model was constructed that included the proposed roles of 2-hydroxy-5-oxoproline as a signal molecule of ammonium assimilation status in leaves, as a stimulator of nitrate uptake by roots and nitrate downloading from the xylem. In summary, a glutamine metabolite made in the ω-amidase pathway stimulated nitrate uptake by roots and was likely to be a signal of ammonium assimilation status in leaves. A chemical synthesis method for 2-hydroxy-5-oxoproline was also developed., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Various complications occur after a biliary-digestive reconstruction. Volvulus of a segment of the biliodigestive loop has not been described. Two patients who underwent biliodigestive bypass, years later, began with sudden and intense abdominal pain, associated with a volvulus with necrosis of a segment of this biliodigestive loop. This complication occurred many years after the initial correction, and manifested with sudden abdominal pain without impaired liver function, as occurred in these patients., (Copyright: © 2023 Permanyer.)

Introduction: Robotic-assisted surgery is gaining popularity because of reported improvement in aesthetic outcomes while reducing the occurrence of complications compared with conventional surgical methods. Deep inferior epigastric perforator (DIEP) flap harvesting has a long track record as a viable procedure for autologous reconstruction of the breast. In this literature review, we describe the feasibility of using the robotic platform in DIEP flap harvest., Methods: The Preferred Reporting Items for Systemic Reviews and Meta-Analysis methodology was to guide the literature review. PubMed and Scopus databases were searched from inception to June 6, 2022. The Medical Subject Heading terms and keywords used to conduct this search are as described: "Robotic AND deep inferior epigastric perforator AND Breast reconstruction.", Results: Seven publications, detailing a total of 56 robotic-assisted DIEP flap harvest procedures, were selected for review. Four publications used the transabdominal preperitoneal approach, whereas 2 exclusively used a totally extraperitoneal approach, and 1 compared the 2 approaches. The measured outcomes included technical feasibility of flap harvest in cadavers, viable flap harvest in live patients, harvest time and pedicle dissection time, pedicle length, fascial incision length, donor site pain, need for postoperative narcotic, donor site morbidity, and hernia formation. Overall, the reviewed articles demonstrated successful DIEP flap harvesting without the need for conversion to the conventional open procedure. Postoperative complications were minimal. Robotic DIEP flap harvest was shown to be safe and there were no reports of donor-site morbidity in the studies reviewed. The main advantages of the robotic approach include decreased postoperative pain and length of hospital stay, along with improved aesthetic outcomes. The main disadvantages are increased operative time and cost., Conclusions: Although at its current iteration, the robotic-assisted DIEP flap is feasible, it may not be practical in all settings. Furthermore, the true benefit of the robotic platform is yet to be determined, as more long-term studies are necessary., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mutations that alter splicing of X-linked ATP6AP2 cause a spectrum of neurodevelopmental and neurodegenerative pathologies including parkinsonism in affected males. All previously reported splicing mutations increase the level of a minor isoform with skipped exon 4 (Δe4) that encodes a functionally deficient protein., Objectives: We investigated the pathogenic mechanism of a novel c.168+6T>A variant reported in a family with X-linked intellectual disability, epilepsy, and parkinsonism. We also analyzed ATP6AP2 splicing defects in brains of carriers of a c.345C>T variant associated with X-linked spasticity and parkinsonism., Methods: We generated induced pluripotent stem cells from patients with c.168+6T>A, reprogrammed them to neural progenitor cells and analyzed them by RNA-Seq and qRT-PCR. We also quantified ATP6AP2 isoforms in the brains of c.345C>T carriers by Nanostring nCounter., Results: The c.168+6T>A increased skipping of ATP6AP2 exon 2 and usage of cryptic intronic donor splice sites. This results in out-of-frame splicing products and a reciprocal 50% reduction in functional full-length ATP6AP2 transcripts. Neural progenitors of patients with c.168+6T>A exhibited downregulated neural development gene networks. Analysis of blood transcriptomes of c.168+6T>A carriers identified potential biomarkers of ATP6AP2 deficiency in non-neural tissues. The c.345C>T variant increased exon 4 skipping with concomitant decrease of full length ATP6AP2 in brains of carriers., Conclusion: A common pathogenic consequence of splicing mutations affecting inclusion of different ATP6AP2 exons is reduction of the functional full-length transcript. The exacerbated ATP6AP2 splicing defect in brains of c.345C>T carriers is consistent with their CNS-restricted clinical presentations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Infections with globally disseminated Shiga toxin-producing Escherichia coli (STEC) of the O113:H21 serotype can progress to severe clinical complications, such as hemolytic uremic syndrome (HUS). Two phylogeographically distinct clonal complexes have been established by multi locus sequence typing (MLST). Infections with ST-820 isolates circulating exclusively in Australia have caused severe human disease, such as HUS. Conversely, ST-223 isolates prevalent in the US and outside Australia seem to rarely cause severe human disease but are frequent contaminants. Following a genomic epidemiology approach, we wanted to gain insights into the underlying cause for this disparity. We examined the plasticity in the genome make-up and Shiga toxin production in a collection of 20 ST-820 and ST-223 strains isolated from produce, the bovine reservoir, and clinical cases. STEC are notorious for assembly into fragmented draft sequences when using short-read sequencing technologies due to the extensive and partly homologous phage complement. The application of long-read technology (LRT) sequencing yielded closed reference chromosomes and plasmids for two representative ST-820 and ST-223 strains. The established high-resolution framework, based on whole genome alignments, single nucleotide polymorphism (SNP)-typing and MLST, includes the chromosomes and plasmids of other publicly available O113:H21 sequences and allowed us to refine the phylogeographical boundaries of ST-820 and ST-223 complex isolates and to further identify a historic non-shigatoxigenic strain from Mexico as a quasi-intermediate. Plasmid comparison revealed strong correlations between the strains' featured pO113 plasmid genotypes and chromosomally inferred ST, which suggests coevolution of the chromosome and virulence plasmids. Our pathogenicity assessment revealed statistically significant differences in the Stx 2a -production capabilities of ST-820 as compared to ST-223 strains under RecA-induced Stx phage mobilization, a condition that mimics Stx-phage induction. These observations suggest that ST-820 strains may confer an increased pathogenic potential in line with the strain-associated epidemiological metadata. Still, some of the tested ST-223 cultures sourced from contaminated produce or the bovine reservoir also produced Stx at levels comparable to those of ST-820 isolates, which calls for awareness and for continued surveillance of this lineage.

Background: Primary prevention strategies for asthma are lacking. Its inception probably starts in utero and/or during the early postnatal period as the developmental origins of health and disease (DOHaD) paradigm suggests., Objectives: The main objective of Nutrition in Early Life and Asthma (NELA) cohort study is to unravel whether the following factors contribute causally to the developmental origins of asthma: (1) maternal obesity/adiposity and foetal growth; (2) maternal and child nutrition; (3) outdoor air pollution; (4) endocrine disruptors; and (5) maternal psychological stress. Maternal and offspring biological samples are used to assess changes in offspring microbiome, immune system, epigenome and volatilome as potential mechanisms influencing disease susceptibility., Population: Randomly selected pregnant women from three health areas of Murcia, a south-eastern Mediterranean region of Spain, who fulfilled the inclusion criteria were invited to participate at the time of the follow-up visit for routine foetal anatomy scan at 19-22 weeks of gestation, at the Maternal-Fetal Medicine Unit of the "Virgen de la Arrixaca" University Clinical Hospital over a 36-month period, from March 2015 to April 2018., Design: Prospective, population-based, maternal-child, birth cohort study., Methods: Questionnaires on exposures and outcome variables were administered to mothers at 20-24 gestation week; 32-36 gestation week; and delivery. Children were surveyed at birth, 3 and 18 months of age and currently at 5 years. Furthermore, physical examinations were performed; and different measurements and biological samples were obtained at these time points., Preliminary Results: Among the 1350 women invited to participate, 738 (54%) were finally enrolled in the study and 720 of their children were eligible at birth. The adherence was high with 612 children (83%) attending the 3 months' visit and 532 children (72%) attending the 18 months' visit., Conclusion: The NELA cohort will add original and unique knowledge to the developmental origins of asthma., (© 2021 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Human papillomavirus (HPV) infections are transmitted through sexual or other close contact and are etiologically associated with epithelial warts, papillomas, and intraepithelial lesions that may progress to cancer. Indeed, 4.8% of the global cancer burden is linked to HPV infection. Highly effective vaccines protect against two to nine of the most medically important HPV genotypes, yet vaccine uptake is inadequate and/or cost prohibitive in many settings. With HPV-related cancer incidence expected to rise over the coming decades, there is a need for effective HPV microbicides. Herein, we demonstrate the strong inhibitory activity of the heparin-neutralizing drug protamine sulfate (PS) against HPV infection. Pretreatment of cells with PS greatly reduced infection, regardless of HPV genotype or virus source. Vaginal application of PS prevented infection of the murine genital tract by HPV pseudovirions. Time-of-addition assays where PS was added to cells before infection, during infection, or after viral attachment demonstrated strong inhibitory activities on early infection steps. No effect on virus infection was found for cell lines deficient in heparan sulfate expression, suggesting that PS binds to heparan sulfate on the cell surface. Consistent with this, prophylactic PS exposure prevented viral attachment, including under low-pH conditions akin to the human vaginal tract. Our findings suggest PS acts dually to prevent HPV infection: prophylactic treatment prevents HPV attachment to host cells, and postattachment administration alters viral entry. Clinical trials are warranted to determine whether protamine-based products are effective as topical microbicides against genital HPVs.

Recent mandates to wear masks in public places across the USA combined with conflicting messaging from the media and government agencies have generated a lot of patient questions surrounding the appropriate use and efficacy of cloth masks. Here, we have organized the evidence in the context of real patient questions and have provided example answers from a physician's perspective. The purpose of this review is to offer healthcare providers with examples of how to respond to patient questions about masks in a way that encourages responsible decision-making. We conclude, based on the evidence showing a benefit for cloth masks and the recent reports supporting a role for aerosols in the transmission of SARS-CoV-2, that cloth masks will be effective when used correctly. We further assert that stronger public messaging surrounding cloth masks in the community setting is needed, and should specify that 2-3 layer, fitted face masks be worn at all times in public as another layer of protection in addition to social distancing, not just when social distancing cannot be maintained., (© 2020. The Author(s).)

Importance: Although early fluid administration has been shown to lower sepsis mortality, positive fluid balance has been associated with adverse outcomes. Little is known about associations in non-intensive care unit settings, with growing concern about readmission from excess fluid accumulation in patients with sepsis., Objective: To evaluate whether positive fluid balance among non-critically ill patients with sepsis was associated with increased readmission risk, including readmission for heart failure., Design, Setting, and Participants: This multicenter retrospective cohort study was conducted between January 1, 2012, and December 31, 2017, among 57 032 non-critically ill adults hospitalized for sepsis at 21 hospitals across Northern California. Kaiser Permanente Northern California is an integrated health care system with a community-based population of more than 4.4 million members. Statistical analysis was performed from January 1 to December 31, 2019., Exposures: Intake and output net fluid balance (I/O) measured daily and cumulatively at discharge (positive vs negative)., Main Outcomes and Measures: The primary outcome was 30-day readmission. The secondary outcomes were readmission stratified by category and mortality after living discharge., Results: The cohort included 57 032 patients who were hospitalized for sepsis (28 779 women [50.5%]; mean [SD] age, 73.7 [15.5] years). Compared with patients with positive I/O (40 940 [71.8%]), those with negative I/O (16 092 [28.2%]) were older, with increased comorbidity, acute illness severity, preexisting heart failure or chronic kidney disease, diuretic use, and decreased fluid administration volume. During 30-day follow-up, 8719 patients (15.3%) were readmitted and 3639 patients (6.4%) died. There was no difference in readmission between patients with positive vs negative I/O (HR, 1.00; 95% CI, 0.95-1.05). No association was detected between readmission and I/O using continuous, splined, and quadratic function transformations. Positive I/O was associated with decreased heart failure-related readmission (HR, 0.80 [95% CI, 0.71-0.91]) and increased 30-day mortality (HR, 1.23 [95% CI, 1.15-1.31])., Conclusions and Relevance: In this large observational study of non-critically ill patients hospitalized with sepsis, there was no association between positive fluid balance at the time of discharge and readmission. However, these findings may have been limited by variable recording and documentation of fluid intake and output; additional studies are needed to examine the association of fluid status with outcomes in patients with sepsis to reduce readmission risk.

Racism is now widely recognized as a fundamental cause of health inequalities in the United States. As such, health scholars have rightly turned their attention toward examining the role of structural racism in fostering morbidity and mortality. However, to date, much of the empirical structural racism-health disparities literature limits the operationalization of structural racism to a single domain or orients the construct around a White/Black racial frame. This operationalization approach is incomprehensive and overlooks the heterogeneity of historical and lived experiences among other racial and ethnic groups. To address this gap, we present a theoretically grounded framework that illuminates core mutually reinforcing domains of structural racism that have stratified opportunities for health in the United States. We catalog instances of structural discrimination that were particularly constraining (or advantageous) to the health of racial and ethnic groups from the late 1400s to present. We then illustrate the utility of this framework by applying it to American Indians or Alaska Natives and discuss the framework's broader implications for empirical health research. This framework should help future scholars across disciplines as they identify and interrogate important laws, policies, and norms that have differentially constrained opportunities for health among racial and ethnic groups., Competing Interests: Competing Interests: None declared., (Copyright © 2021, Ethnicity & Disease, Inc.)

Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools., Competing Interests: Declaration of interests J.K.M., L.T.G., E.E.H., H.Z., B.T., E.L., J.T.T., and B.P.L. are inventors on several U.S. patent applications related to this work. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

A new protocol for rapid SPECT/CT blood pool imaging consisting of fewer image-angle acquisitions (fewer-angle SPECT/CT, or FASpecT/CT) was evaluated for localization of focal sites of soft-tissue inflammation, infection, and osteomyelitis. Methods: Immediately after dynamic flow and standard planar blood pool imaging with 99m Tc-methylene diphosphonate, FASpecT/CT was performed with a dual-head γ-camera consisting of 6 steps over 360°, 12 total images with 30° of separation between angles, and 30 s per image, requiring a total imaging time of approximately 3 min. Images were reconstructed using iterative ordered-subset expectation maximization. Before use in a patient-care setting, various FASpecT/CT acquisition protocols were modeled using a phantom to determine the minimum number of stops and the stop duration required to produce a reliable image. Results: FASpecT/CT images provided excellent 3-dimensional localization of spine osteomyelitis, soft-tissue infection of the foot, and tendonitis of the hand and foot using a 3-min image acquisition time. The FASpecT/CT acquisition protocol required 1.3-3.5 min, including camera movement time. This was a reduction of 72%-90% from the time required for the standard 60-angle, 20-s SPECT/CT acquisition. Conclusion: The ability of FASpecT/CT blood pool images to help localize focal sites of hyperemia and inflammation can increase exam sensitivity and specificity. Additionally, using a FASpecT/CT protocol decreases imaging time by up to 90%., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Numerous studies have revealed the impact of umbilical cord (UC) length on fetal perfusion; abundant data implicate abnormal UC length to neurological delay and subsequent poor prognoses for fetuses and newborns. Indeed, our group previously developed theoretical approximations that contributed to formulas capable of explaining the impact of UC length on cardiac output., Methods: We performed an observational study that measured the pulsatility index and flow velocity in umbilical arteries. A special Doppler measured proximal and distal indexes in both arteries. After birth, medical staff measured complete UC length. We obtained maternal and neonatal outcomes from clinical records., Results: Our study enrolled 20 pregnant mothers. We found that flow velocities in the two edges were different: fetal edges exhibited greater velocity in the majority of cases; but, when we compared pressure differentials (ΔP), the pulsatility index was significantly related to umbilical cord length., Conclusions: Fetal perfusion, welfare, and viability are related to UC function as the conveyor of all fetal volemia. Excessive UC length affects cardiac dynamics and increases peripheral vascular resistance. Further studies could validate routine use of the differential proximal and distal measurements proposed in this article, and their implications in in utero fetal heart function. We also hope that early diagnosis or UC alterations could alert neonatologists and obstetricians to clinical conditions of the fetus.

Expertise in the delivery of effective local analgesia is critical to the success of in-office procedures. Here's how to optimize patient outcomes and satisfaction.

Background: The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies., Methods: We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants., Results: PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intracardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in 2 PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared nonsynonymous mutations, and no correlation by gene expression., Conclusions: We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hospital readmissions with 30 days after vascular surgical interventions have been associated with increased morbidity, mortality, and cost. Readmission rates, now a Centers for Medicare and Medicaid Services quality measure, have been studied in databases that have excluded certain payer types and states and have not accounted for readmission to a hospital different from that of the index admission. More accurate and nationally representative data are needed, because this fragmentation of care could lead to flawed conclusions. The purpose of the present study was to examine the incidence and risk factors for readmission to a nonindex hospital for patients admitted for claudication or critical limb ischemia (CLI). We also examined how this disruption of patient care affects mortality., Methods: The 2013 to 2014 Nationwide Readmissions Database was queried for all patients admitted for claudication or CLI who had undergone angioplasty, lower extremity bypass, or aortobifemoral bypass. The outcomes of interest were 30- and 365-day readmission rates to any hospital, 30- and 365-day readmission rates to a nonindex hospital, and mortality rates. Multivariable logistic regression was used to identify risk factors for readmission to a nonindex hospital. The most common readmission diagnoses and diagnosis-related groups were identified., Results: A total of 92,769 patients had been admitted with peripheral vascular disease (33,055 with claudication and 59,714 with CLI). The 30- and 365-day readmission rate was 8.97% and 21.49% and 19.26% and 40.36%, for claudication and CLI, respectively. Of the 30- and 365-day readmissions, 20.47% and 24.92% had occurred at a nonindex hospital, respectively. Significantly higher mortality rates were found for patients with 30- or 365-day readmissions to different hospitals (odds ratio, 1.4 and 1.8, respectively). Multivariable analysis revealed that procedural indication and angioplasty are not significant risk factors for readmission to a different hospital. However, female sex, length of stay >7 days, and Charlson Comorbidity Index >3 remained significant risk factors for nonindex readmissions. The most common disease groups for nonindex readmission were "septicemia and disseminated infections" (6.5%), "heart failure" (6.4%), "other vascular procedures" (6.1%), and "amputation of lower limb except toes" (4.0%)., Conclusions: Previously unreported, ≥1 in 4 readmissions after lower extremity vascular procedures for peripheral vascular disease will occur at a nonindex hospital. This fragmentation of care is associated with increased mortality and has serious implications for guiding outcome and quality measures. With a sizeable portion of patients missed by current metrics, concern exists that providers are using flawed data. Further study into social- and patient-specific risk factors might provide methods to prevent these readmissions and improve outcomes in this difficult patient population., (Copyright © 2019. Published by Elsevier Inc.)

Papillomaviruses (PVs) were the first viruses recognized to cause tumors and cancers in mammalian hosts by Shope, nearly a century ago (Shope and Hurst, 1933). Over 40 years ago, zur Hausen (1976) first proposed that human papillomaviruses (HPVs) played a role in cervical cancer; in 2008, he shared the Nobel Prize in Medicine for his abundant contributions demonstrating the etiology of HPVs in genital cancers. Despite effective vaccines and screening, HPV infection and morbidity remain a significant worldwide burden, with HPV infections and HPV-related cancers expected increase through 2040. Although HPVs have long-recognized roles in tumorigenesis and cancers, our understanding of the molecular mechanisms by which these viruses interact with cells and usurp cellular processes to initiate infections and produce progeny virions is limited. This is due to longstanding challenges in both obtaining well-characterized infectious virus stocks and modeling tissue-based infection and the replicative cycles in vitro . In the last 20 years, the development of methods to produce virus-like particles (VLPs) and pseudovirions (PsV) along with more physiologically relevant cell- and tissue-based models has facilitated progress in this area. However, many questions regarding HPV infection remain difficult to address experimentally and are, thus, unanswered. Although an obligatory cellular uptake receptor has yet to be identified for any PV species, Rab-GTPases contribute to HPV uptake and transport of viral genomes toward the nucleus. Here, we provide a general overview of the current HPV infection paradigm, the epithelial differentiation-dependent HPV replicative cycle, and review the specifics of how HPVs usurp Rab-related functions during infectious entry. We also suggest other potential interactions based on how HPVs alter cellular activities to complete their replicative-cycle in differentiating epithelium. Understanding how HPVs interface with Rab functions during their complex replicative cycle may provide insight for the development of therapeutic interventions, as current viral counter-measures are solely prophylactic and therapies for HPV-positive individuals remain archaic and limited.

Background: The safety and feasibility of sterile, acellular pulley allografts in reconstruction has been previously demonstrated. Comparisons with tendon-based techniques for pulley reconstruction have not been reported. We hypothesized that the use of allograft pulleys would result in reduced procedural time and equivalent clinical outcomes as compared with traditional tendon-based reconstructive techniques., Methods: All cases of pulley reconstruction using either allograft pulleys or tendon-based pulley reconstruction between November 2013 and November 2015 were reviewed. Patients who underwent concomitant procedures were excluded. Patient demographics, comorbidities, operative details (tourniquet and total operative times, number of pulleys repaired), postoperative complications (surgical site infection, reoperation, stiffness, and persistent pain), disability of the arm, shoulder and hand scores, and follow-up data were recorded. A P value of <0.05 was considered significant., Results: Fifteen pulleys in 10 patients were reconstructed: 5 tendon-based and 5 with allograft. Average length of follow-up was 12.5 ± 2.9 months. There was no difference in patient demographic factors or comorbidities between groups. The most common indication for surgery was trauma. Four of 5 patients in the allograft group had multiple pulleys reconstructed versus 1 in the tendon-based group. One patient in the tendon-based group required reoperation versus 0 in the allograft group. Total operative and tourniquet times were significantly reduced in the allograft group (46 ± 5.5 vs 89 ± 12.9 minutes and 34 ± 6.8 vs 63 ± 5.3 minutes; P = 0.015 and 0.014). Postoperative disability of the arm, shoulder and hand scores were lower in the allograft group (56.8 vs 3.6, P = 0.11). There was no significant difference in postoperative range of motion between groups., Conclusion: Pulley reconstruction with allograft is an efficient, technically feasible, reconstructive technique that adheres to the principle of replacing like with like, while eliminating donor site morbidity. Overall operative and tourniquet times were significantly shorter using allograft pulleys for pulley reconstruction.