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Fall risk is an acknowledged but relatively understudied concern for older patients undergoing shoulder surgery. The cause is multifactorial, and it includes advanced age, impaired upper extremity function, use of shoulder abduction braces, and postoperative use of opioid medications. No previous study has examined preoperative fall risk in patients undergoing elective shoulder surgery. Previous literature looking at fall risk in elective orthopedic procedures has predominantly focused on falls occurring in the hospital setting, although falls have also been shown to occur in the outpatient setting. Gait speed and Timed Up and Go (TUG) are well-researched functional measures in the aging population with established cutoff scores indicating increased fall risk. The purpose of this study was to quantify gait speed and TUG scores in a series of patients who were scheduled to undergo either rotator cuff repair (RCR) or total shoulder arthroplasty (TSA) in order to assess overall risk of fall in these populations.A total of 198 patients scheduled for TSA or RCR surgery were evaluated preoperatively from multiple outpatient physical therapy clinics within Greenville, South Carolina. The TUG score (14 seconds considered high fall risk) and 10 Meter Walk test (0.7 m/s considered high risk for falls) were recorded for each patient. Patient-reported outcomes were also collected, including Veteran's Rand 12 Physical Component and Mental Component Scores, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score, and the Single Assessment Numeric Evaluation.Patients undergoing TSA (n = 80; 65.4 ± 11.4 years) were older than those undergoing RCR (n = 118; 59.0 ± 14.2 years). Fifty-nine percent of all patients were classified as being a high risk for falls based on gait speed0.7 m/s. Patients in the TSA group were more likely to display preoperative fall risk compared to patients in the RCR group (62% vs. 38%; χBoth patient groups demonstrated a high rate of fall risk in preoperative evaluation. Patients undergoing TSA more often displayed fall risk compared with patients undergoing RCR. Although patients in the TSA group were older, there was no association between age or ambulatory status and fall risk.Our results suggest that fall risk screening may be important for patients undergoing TSA and RCR surgeries. The higher fall risk in the TSA group may be an important consideration as this procedure shifts toward outpatient status.

Adenosquamous carcinoma of the pancreas (ASCP) is a rare subtype of pancreatic adenocarcinoma. The aim of this study was to investigate the characteristics and outcomes of ASCP in comparison to pancreatic ductal adenocarcinoma (PDAC).All patients with ASCP treated between December 2001 and December 2017 were identified from a prospective database. Clinicopathological and follow-up data were analyzed. A nested case-control-study with matched-pair analysis was performed to compare overall survival of ASCP and PDAC.Of 4009 patients undergoing surgery for pancreatic adenocarcinoma 91 patients had ASCP. Compared to PDAC ASCP were larger (4.0 vs. 3.2 cm; p 0.0001), more frequently involved lymph nodes (88% vs. 78%; p = 0.0216), more frequently showed poor differentiation (G3: 79% vs. 36%; p 0.0001) and more frequently were located in the pancreatic tail (19% vs. 10%; p = 0.0179). Overall median post-resection-survival was shorter in ASCP (10.8 vs. 20.5 months in PDAC; p = 0.0085), but 5-year survival rates were comparable (18.2% vs. 17.5%). After matching for the unevenly distributed prognostic factors survival after resection of ASCP and PDAC was comparable (p = 0.8301). Localization in the head or several parts of the pancreas, high CA 19-9 levels, and M1 disease were independent predictors of survival in patients with ASCP.ASCP is more aggressive with poorer differentiation and higher rates of lymph node metastases compared to PDAC. In spite of a shorter median survival, 5-year survival rates after surgical resection of about 18% can be expected in ASCP and support resection as part of a multimodal therapy as the treatment of choice in this rare cancer.

Introduction Multidrug-resistant (MDR) Gram-negative infections complicate care of combat casualties. We describe the clinical characteristics, resistance patterns, and outcomes of Pseudomonas aeruginosa infections in combat casualties. Methods Combat casualties included in the Trauma Infectious Disease Outcomes Study with infections with and without P. aeruginosa isolation during initial hospitalization were compared. Pseudomonas aeruginosa from initial wound, blood, and serial isolates (≥7 days from previous isolate) collected from June 2009 through February 2014 was subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and whole genome sequencing for assessing clonality. Multidrug resistance was determined using the CDC National Healthcare Safety Network definition. Results Of 829 combat casualties with infections diagnosed during initial hospitalization, 143 (17%) had P. aeruginosa isolated. Those with P. aeruginosa were more severely injured (median Injury Severity Score 33 [interquartile range (IQR) 27-45] vs 30 [IQR 18.5-42]; P Conclusions Pseudomonas aeruginosa continues to be a major cause of morbidity, affecting severely injured combat casualties, with emergent antimicrobial resistance upon serial isolation. Among MDR P. aeruginosa, active antimicrobials remain the oldest and most toxic. Despite ongoing efforts, outbreaks are still noted, reinforcing the crucial role of antimicrobial stewardship and infection control.

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the “Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes” trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.

Background The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors underlying both reduced penetrance and the disease mechanism of DYT-THAP1 are largely unknown. Methods We performed transcriptome analysis on 29 cortical neuronal precursors derived from human-induced pluripotent stem cell lines generated from manifesting and nonmanifesting THAP1 mutation carriers and control individuals. Results Whole transcriptome analysis showed a penetrance-linked signature with expressional changes more pronounced in the group of manifesting (MMCs) than in nonmanifesting mutation carriers (NMCs) when compared to controls. A direct comparison of the transcriptomes in MMCs versus NMCs showed significant upregulation of the DRD4 gene in MMCs. A gene set enrichment analysis demonstrated alterations in various neurotransmitter release cycle pathways, extracellular matrix organization, and deoxyribonucleic acid methylation between MMCs and NMCs. When specifically considering transcription factors, the expression of YY1 and SIX2 differed in MMCs versus NMCs. Further, THAP1 was upregulated in the group of MMCs. Conclusions To our knowledge, this is the first report systematically analyzing reduced penetrance in DYT-THAP1 in a human model using transcriptomes. Our findings indicate that transcriptional alterations during cortical development influence DYT-THAP1 pathogenesis and penetrance. We reinforce previously linked pathways including dopamine and eukaryotic translation initiation factor 2 alpha signaling in the pathogenesis of dystonia including DYT-THAP1 and suggest extracellular matrix organization and deoxyribonucleic acid methylation as mediators of disease protection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Operators have spent $84 billion Canadian dollars in exploration, development, and production offshore Newfoundland, Canada, between 1966 and 2019, and have produced about 2 billion barrels of an estimated 3.3 billion barrels recoverable oil. Four major projects have been developed—Hibernia, Terra Nova, White Rose/North Amethyst, and Hebron—using two development concepts, gravity-base structures and floating production storage and offloading vessels. The region is characterized by severe storm and sea conditions, including the presence of icebergs, which challenge all aspects of exploration and development. From 1998 to 2019, exploration and delineation drilling cost averaged $90.9 million per well and $26,494 per meter drilled. Development wells drilled from mobile offshore drilling units over the same period averaged $91.1 million per producer well and $68.8 million per injector well. Regional development cost was $32.5/bbl since the start of production and is expected to fall to $22/bbl when recoverable volumes circa 2020 have been extracted. Average regional production cost from 2006 to 2019 is estimated at $23.4/bbl and ranges from $16.8/bbl at Hibernia to about $35/bbl at Terra Nova and White Rose. This is the first detailed evaluation of exploration, development, and production cost offshore Newfoundland.

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3. This review highlights the molecular characteristics of TRα2, proposed mechanisms that regulate alternative splicing and indications pointing towards an antagonistic function of this TR isoform in vitro and in vivo. Moreover, remaining knowledge gaps and major challenges that complicate TRα2 characterization, as well as future strategies to fully uncover its physiological relevance, are discussed.

CRISPR gene editing and control systems continue to emerge and inspire novel research and clinical applications. Advances in CRISPR performance such as optimizing the duration of activity in cells, tissues, and organisms, as well as limiting off-target activities, have been extremely important for expanding the utility of CRISPR-based systems. By investigating the effects of various chemical modifications in guide RNAs (gRNAs) at defined positions and combinations, we find that 2'

Quantifying the change in field expected ultimate recovery across time is an old and complex topic fraught with ambiguity and misinterpretation. In this paper, changes in recovery estimates performed by the Bureau of Ocean Energy Management in the US Gulf of Mexico are evaluated based on 782 offshore fields that began producing after 1975 and ceased production before 2017. At the time of first production, field expected ultimate recovery estimates totaled 6.3 billion barrels oil equivalent (38.6 exajoules), but by the end of their life, the fields produced 8.5 billion barrels oil equivalent (52 exajoules), a 35% growth. On an individual field basis, however, median recovery estimates grew less than 2%. The purpose of this paper is to explain the differences in these two statistics and quantify how expected ultimate recovery is influenced by field age, discovery year, reserve category, peak ratio, product type, size, and water depth to understand better the contribution of individual factors in reserves evaluation. Consistent interpretation of reserves category is probably the most important factor in application. Field age and size are positively correlated with changes in expected ultimate recovery in both the shallow water and deepwater regions of the US Gulf of Mexico, pre- and post-1988 evaluation periods are a significant factor, and a development variable referred to as peak ratio exhibits a meaningful correspondence. The results of this analysis show that Bureau of Ocean Energy Management procedures for expected ultimate recovery estimation in the US Gulf of Mexico post-1988 are consistent with the application of probable reserves classifications; these highlight the need for a precise understanding of factor inputs in reserves growth studies.

In this article, we discuss the ways in which psychology educators can assist students who have color vision deficiency (CVD). We outline basic information concerning CVD, offer tips for instructors to help students with CVD access content materials in the classroom, and suggest class activities to help all psychology students learn about CVD.

Trawl fishing constitutes an important part of the marine fisheries sector in Southeast Asia. It provides livelihoods and food for millions of people in coastal communities as well as feed for the ...

PURPOSE: Evaluation of [68Ga]NODAGA-duramycin as a positron emission tomography (PET) tracer of cell death for whole-body detection of chemotherapy-induced organ toxicity.PROCEDURES: Tracer specificity of Ga-68 labeled NODAGA-duramycin was determined in vitro using competitive binding experiments. Organ uptake was analyzed in untreated and doxorubicin, busulfan, and cisplatin-treated mice 2 h after intravenous injection of [68Ga]NODAGA-duramycin. In vivo data were validated by immunohistology and blood parameters.RESULTS: In vitro experiments confirmed specific binding of [68Ga]NODAGA-duramycin. Organ toxicities were detected successfully using [68Ga]NODAGA-duramycin PET/X-ray computed tomography (CT) and confirmed by immunohistochemistry and blood parameter analysis. Organ toxicities in livers and kidneys showed similar trends in PET/CT and immunohistology. Busulfan and cisplatin-related organ toxicities in heart, liver, and lungs were detected earlier by PET/CT than by blood parameters and immunohistology.CONCLUSION: [68Ga]NODAGA-duramycin PET/CT was successfully applied to non-invasively detect chemotherapy-induced organ toxicity with high sensitivity in mice. It, therefore, represents a promising alternative to standard toxicological analyses with a high translational potential.

The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1–3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6–8. ZBP1 mediates host defence against some viruses6,7,9–14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Zα-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Zα-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions—particularly in individuals with mutations in RIPK1 and CASP817–20. Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids—such as those of endogenous retroelements—through its Zα domains.

The elimination of unwanted catch in mixed species fisheries is technically challenging given the complexity of fish behaviour within nets. Most approaches to date have employed technologies that modify the nets themselves or use physical sorting grids within the gear. There is currently increasing interest in the use of artificial light to either deter fish from entering the net, or to enhance their escapement from within the net. Here, we evaluated the differences in catch retained in a standard otter trawl, relative to the same gear fitted with a square mesh panel, or a square mesh panel fitted with LEDs. We found that the selectivity of the gear differed depending on water depth. When using a square mesh panel in shallow depths of 29–40 m the unwanted bycatch of whiting and haddock was reduced by 86% and 58% respectively. In deep, darker water (45–95 m), no change in catch was observed in the square-mesh panel treatment, however when LEDs were added to the square-mesh panel, haddock and flatfish catches were reduced by 47% and 25% respectively. These findings demonstrate the potential to improve the performance of bycatch reduction devices through the addition of light devices to enhance selectivity. The results also highlight species-specific and site-specific differences in the performance of bycatch reduction devices, and hence a more adaptive approach to reduce bycatch is probably required to maximize performance.

Wearable devices offer a promise of immense impact on worldwide global health by offering the potential for non-invasive, constantly vigilant, and low-cost monitoring of individual condition and fundamental advances in guiding healthcare. The urgency of this objective for its individual and societal benefits will attract an expanding community of researchers from backgrounds in nearly every field of computing. This article describes the unprecedented benefits and opportunities for computing research in wearable devices and the multidisciplinary challenges that have not been encountered individually or combined together in previous research. This article is focused on providing guidance to the new community of healthcare in computing researchers who will both create a new field and forge transformative solutions for healthcare delivery to a worldwide population.

Public Support of Private Innovation: An Initial Assessment of the North Carolina SBIR/STTR Phase I Matching Funds Program

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.