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Background: Surrogate Decision-Makers (surrogates) are frequently employed in decision-making for critically ill adults. There are insufficient data considering the surrogate experience, stress, and potential for mitigation., Methods: An anonymous online survey queried (1) medical situation (2) total stress (3) demographics (4) potential factors, including sources of information about patient wishes, external sources of support or competing stressors, and their interactions with the medical team through the experience., Results: 108 respondents were included; 91 completed all items. Most respondents ranked their experience as a surrogate as one of the most stressful experiences of their lives; this was associated with whether it was an end-of-life decision ( P = .003), Respondent Religion ( P = .015), or religious or spiritual beliefs ( P = .024), and having their own health problems (P = .008). On individual Likert responses, surrogates reported significant stress mitigation when they felt they had been helpful ( P < .001), knew the patient's wishes ( P = .0011), specifically discussed patient wishes ( P < .001), or patient's wishes were documented ( P < .001). Items about surrogate-team interaction also met significance, including the physician being communicative and available (P < .001), respectful ( P = .007), honest ( P < .001), and validating ( P = .001)., Conclusions: Surrogate stress is an evolving area for research. Significant factors included relationship with the medical team, making this an important area for HPM to play a key role in mitigating surrogate stress., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Glioblastoma brain tumors represent an aggressive form of gliomas that is hallmarked by being extremely invasive and aggressive due to intra and inter-tumoral heterogeneity. This complex tumor microenvironment makes even the newer advancements in glioblastoma treatment less effective long term. In developing newer treatment technologies against glioblastoma, one should tailor the treatment to the tumor microenvironment, thus allowing for a more robust and sustained anti-glioblastoma effect. Here, we present a novel gold nanoparticle therapy explicitly designed for bioactivity against glioblastoma representing U87MG cell lines. We employ standard conjugation techniques to create oligonucleotide-coated gold nanoparticles exhibiting strong anti-glioblastoma behavior and optimize their design to maximize bioactivity against glioblastoma. Resulting nanotherapies are therapy specific and show upwards of 75% inhibition in metabolic and proliferative activity with stark effects on cellular morphology. Ultimately, these gold nanotherapies are a good base for designing more multi-targeted approaches to fighting against glioblastoma.

We engineered an ultrasensitive reporter of p16 INK4a , a biomarker of cellular senescence. Our reporter detected p16 INK4a -expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these p16 INK4a+ fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, p16 INK4a expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for p16 INK4a+ fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.

Aging is the final stage of development with stereotyped changes in tissue morphology. These age-related changes are risk factors for a multitude of chronic lung diseases, transcending the diverse pathogenic mechanisms that have been studied in disease-specific contexts. Two of the hallmarks of aging include inflammation and cellular senescence, which have been attributed as drivers of age-related organ decline. While these two age-related processes are often studied independently in the same tissue, there appears to be a reciprocal relationship between inflammation and senescence, which remodels the aging tissue architecture to increase susceptibility to chronic diseases. This review will attempt to address the "chicken or the egg" question as to whether senescence drives inflammation in the aging lung, or vice versa, and whether the causality of this relationship has therapeutic implications for age-related lung diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Allen, Reyes, Lee and Peng.)

Heterogeneity in the behavior of genetically and developmentally equivalent cells is becoming increasingly appreciated. There are several sources of cellular heterogeneity, including both intrinsic and extrinsic noise. We found that some aspects of heterogeneity in the response of macrophages to bacterial lipopolysaccharide (LPS) were due to intercellular desynchronization of the molecular clock, a cell-intrinsic oscillator. We found that the ratio of the relative expression of two clock genes, Nfil3 and Dbp , expressed in opposite phases of the clock, determined the fraction of cells that produced the cytokine IL-12p40 in response to LPS. The clock can be entrained by various environmental stimuli, making it a mechanism by which population-level heterogeneity and the inflammatory response can be regulated., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To estimate the hospital revisit rate of patients diagnosed with conversion disorder (CD)., Methods: Using administrative data, we identified all patients discharged from California, Florida and New York emergency departments (EDs) and acute care hospitals between 2005 and 2011 with a primary discharge diagnosis of CD. Patients discharged with a primary diagnosis of seizure or transient global amnesia (TGA) served as control groups. Our primary outcome was the rate of repeat ED visits and hospital admissions after initial presentation. Poisson regression was used to compare rates between diagnosis groups while adjusting for demographic characteristics., Results: We identified 7946 patients discharged with a primary diagnosis of CD. During a mean follow-up of 3.0 (±1.6) years, patients with CD had a median of three (IQR, 1-9) ED or inpatient revisits, compared with 0 (IQR, 0-2) in patients with TGA and 3 (IQR, 1-7) in those with seizures. Revisit rates were 18.25 (95% CI, 18.10 to 18.40) visits per 100 patients per month in those with CD, 3.90 (95% CI, 3.84 to 3.95) in those with TGA and 17.78 (95% CI, 17.75 to 17.81) in those with seizures. As compared to CD, the incidence rate ratio for repeat ED visits or hospitalisations was 0.89 (95% CI, 0.86 to 0.93) for seizure disorder and 0.32 (95% CI 0.31 to 0.34) for TGA., Conclusions: CD is associated with a substantial hospital revisit rate. Our findings suggest that CD is not an acute, time-limited response to stress, but rather that CD is a manifestation of a broader pattern of chronic neuropsychiatric disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P  =  1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies., Competing Interests: CB Do, N Eriksson, and JY Tung are employed by 23andMe and own stock options in the company. MJ Farrer and Mayo Foundation received royalties from H.Lundbeck A/S and Isis Pharmaceuticals. In addition, MJ Farrer has received an honorarium for a seminar at Genzyme. T Gasser has received consultancy fees from Cephalon and Merck-Serono, grants from Novartis, payments for lectures including service on speakers' bureaus from Boehringer Ingelheim, Merck-Serono, UCB, and Valean, and holds patents NGFN2 and KASPP. JA Hardy has received consulting fees or honoraria from Eisai and his institute has received consulting fees or honoraria from Merck-Serono. DM Maraganore has received extramural research funding support from the National Institutes of Health (2R01 ES10751), the Michael J. Fox Foundation (Linked Efforts to Accelerate Parkinson Solutions Award, Edmond J. Safra Global Genetics Consortia Award), and from Alnylam Pharmaceuticals and Medtronic (observational studies of Parkinson's disease). DM Maraganore has also received intramural research funding support from the Mayo Clinic and from NorthShore University Health System. DM Maraganore filed a provisional patent for a method to predict Parkinson's disease. This provisional patent is unlicensed. He also filed a provisional patent for a method to treat neurodegenerative disorders. That provisional patent has been licensed to Alnylam Pharmaceuticals and DM Maraganore has received royalty payments in total of less than $20,000. K Stefansson has received grants from deCODE.

Human faces exhibit enormous variation. When pathological conditions are superimposed on normal variation, a nearly unbroken series of facial morphologies is produced. When viewed in full, this spectrum ranges from cyclopia and hypotelorism to hypertelorism and facial duplications. Decreased Hedgehog pathway activity causes holoprosencephaly and hypotelorism. Here, we show that excessive Hedgehog activity, caused by truncating the primary cilia on cranial neural crest cells, causes hypertelorism and frontonasal dysplasia (FND). Elimination of the intraflagellar transport protein Kif3a leads to excessive Hedgehog responsiveness in facial mesenchyme, which is accompanied by broader expression domains of Gli1, Ptc and Shh, and reduced expression domains of Gli3. Furthermore, broader domains of Gli1 expression correspond to areas of enhanced neural crest cell proliferation in the facial prominences of Kif3a conditional knockouts. Avian Talpid embryos that lack primary cilia exhibit similar molecular changes and similar facial phenotypes. Collectively, these data support our hypothesis that a severe narrowing of the facial midline and excessive expansion of the facial midline are both attributable to disruptions in Hedgehog pathway activity. These data also raise the possibility that genes encoding ciliary proteins are candidates for human conditions of hypertelorism and FNDs.

In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.

The aim of this study was to assess a stroke clinic's performance in the diagnosis of hyperlipidemia and more specifically to evaluate the effectiveness of statins in patients with cerebrovascular disease not enrolled in a research study. The records of 370 consecutive patients seen at a stroke clinic over a 4-year period were reviewed, and information regarding neurologic diagnosis, lipid profile, and use and type of cholesterol-lowering medication was abstracted. Hyperlipidemia was defined as a total cholesterol level equal to or more than 200 mg/dL. Forty-eight patients meeting specific criteria were further analyzed to monitor the effects of statins. Cholesterol testing was obtained in 324 patients (88%) and 178 (55%) were hyperlipidemic, but only 86 (48%) patients received treatment. The mean cholesterol level of the 48 patients dropped from 246.2 mg/dL to 197.1 mg/dL (P < .0001) after the initiation of statin therapy, and significant reductions were present in subgroups with pretreatment levels of 200 to 249 mg/dL and 250 to 299 mg/dL. Of the 21 patients with repeated cholesterol testing more than 6 months after the first posttreatment test, only 11 (52%) maintained a level below 200 mg/dL. Effective control of hyperlipidemia can be achieved in patients with cerebrovascular disease, but not all are adequately tested or treated. Improved physician awareness and more effective health care delivery systems are needed.

Methsuximide (MSM; Celontin) was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. Drowsiness, gastrointestinal disturbance, hiccups, irritability, and headache were the common side effects of MSM. No serious toxicity occurred. N-desmethylmethsuximide was the principal substance detected in plasma and had the following pharmacokinetic values: accumulation half-life, 49.7 hours; time to steady state, 10.4 days; elimination half-life, 72.2 hours; therapeutic range of plasma concentration, 10 to 30 mg per liter. Plasma concentrations of phenytoin and phenobarbital derived from primidone rose significantly (p less than 0.05) after addition of MSM.

In vitro studies indicate that [(57)Co]cobalamin (Cbl) is preferentially bound to salivary R protein as opposed to intrinsic factor (IF) and that [(57)Co]Cbl bound to R protein is not transferred to IF at either pH 2 or pH 8. Incubation of R protein-[(57)Co]Cbl with pancreatic proteases causes a partial degradation of the R protein moiety and a rapid transfer of [(57)Co]Cbl to IF. We have postulated that the etiology of Cbl malabsorption in pancreatic insufficiency is an inability to partially degrade R protein because of a lack of pancreatic proteases. We have tested this hypothesis by determining the ability of a nonradioactive Cbl analogue, bound with high affinity by R protein but not by IF, to correct the malabsorption of [(57)Co]Cbl in patients with pancreatic insufficiency.R protein bound the Cbl analogue known as cobinamide with affinities that were the same and only 14-fold lower than those for Cbl at pH 8 and pH 2, respectively. Cobinamide was bound by IF with affinities that were 600,000- and 10,000-fold lower than those for Cbl at pH 8 and 2, respectively. The addition of 125 pmol of nonradioactive cobinamide to 0.5 pmol of [(57)Co]Cbl before being added to 1 pmol of R protein and 1 pmol of IF, markedly inhibited the ability of R protein to compete with IF for binding the [(57)Co]Cbl. Similar results were obtained with freshly aspirated gastric juice. This change was essentially indistinguishable from that observed previously when R protein or R protein-[(57)Co]Cbl was incubated in vitro with trypsin. The oral administration of 100 nmol of nonradioactive cobinamide in Schilling tests was equivalent to trypsin in its ability to completely correct the malabsorption of 0.4 nmol of [(57)Co]Cbl in three patients with pancreatic insufficiency. The fact that both trypsin and nonradioactive cobinamide inhibit the ability of R protein to compete with IF for [(57)Co]Cbl binding in vitro, and correct the mal-absorption of [(57)Co]Cbl in patients with pancreatic insufficiency in vivo, supports our hypothesis that the primary defect in Cbl absorption in this disease is an inability to partially degrade R protein because of a lack of pancreatic proteases.

Since R protein binds cobalamin (vitamin B12) and cobalamin analogues, whereas intrinsic factor is highly specific for true cobalamin, we compared the serum cobalamin values obtained with these proteins in radioisotope dilution assays. With R protein, eight of 21 patients with cobalamin deficiency had serum cobalamin levels (mean, 204, range, 85 to 355 pg per milliliter) that overlapped with values for 74 normal subjects (mean, 576, range, 220 to 1230). With intrinsic factor, no patient values (mean, 36, range, less than 10 to 78 pg per milliliter) overlapped with the normal values (mean, 322, range, 130 to 785). Paper chromatography showed that these differences were due to the presence of cobalamin analogues. R protein constituted 51 to 85 per cent of the cobalamin-binding protein in 10 commercial serum cobalamin assay kits, which were said to contain "intrinsic factor". Human plasma contains cobalamin analogues that can mask cobalamin deficiency with current radioisotope dilution assays.