Routine Elective Gastrojejunostomy Tube Changes Are Associated With Reduced Tube Complications and Radiation Exposure.

Gastrojejunostomy tubes (GJTs) can be a long-term solution for patients with intragastric feeding intolerance. Our retrospective study of 101 patients correlates the frequency of routine and urgent GJT changes, as well as complications and radiation exposure. Over a 2.75-year median duration, 60%, 33%, and 28% of patients had >1 episodes of a tube dislodgement/malpositioning, blockage, or leakage, respectively. Aspiration pneumonia hospital admission was required for 23% of patients. Patients with <1 routine tube change/year had more urgent changes/year (3.0) compared to patients with 1-2 (1.2) or >2 (0.8) routine yearly change. These patients required more frequent sedation for tube placement (21% vs 4.7%, P = 0.03) and experienced greater annual radiation exposure (9599 vs 304.5 and 69.1 µGym 2 , P = 0.01 and 0.008, respectively). Overall, aiming for a routine tube change at least every 6-12 months is associated with fewer urgent changes and complications as well as reduced radiation exposure and sedation requirements.

A stochastic and dynamical view of pluripotency in mouse embryonic stem cells.

Pluripotent embryonic stem cells are of paramount importance for biomedical sciences because of their innate ability for self-renewal and differentiation into all major cell lines. The fateful decision to exit or remain in the pluripotent state is regulated by complex genetic regulatory networks. The rapid growth of single-cell sequencing data has greatly stimulated applications of statistical and machine learning methods for inferring topologies of pluripotency regulating genetic networks. The inferred network topologies, however, often only encode Boolean information while remaining silent about the roles of dynamics and molecular stochasticity inherent in gene expression. Herein we develop a framework for systematically extending Boolean-level network topologies into higher resolution models of networks which explicitly account for the promoter architectures and gene state switching dynamics. We show the framework to be useful for disentangling the various contributions that gene switching, external signaling, and network topology make to the global heterogeneity and dynamics of transcription factor populations. We find the pluripotent state of the network to be a steady state which is robust to global variations of gene switching rates which we argue are a good proxy for epigenetic states of individual promoters. The temporal dynamics of exiting the pluripotent state, on the other hand, is significantly influenced by the rates of genetic switching which makes cells more responsive to changes in extracellular signals.

Reverse transduction can improve efficiency of AAV vectors in transduction-resistant cells.

Reverse transduction, also known as substrate-mediated gene delivery, is a strategy in which viral vectors are first coated onto a surface that subsequently comes into contact with mammalian cells. The cells internalize the surface-attached vectors, resulting in transgene expression. We hypothesized that forcing the interaction between cells and adeno-associated virus (AAV) vectors through a reverse transduction format would increase in vitro gene delivery efficiencies of the vectors in transduction-resistant cells. We tested this hypothesis by comparing the gene delivery efficiencies of three AAV serotypes using either standard or reverse transduction approaches. Our study reveals reverse transduction of AAV7 and AAV9 can significantly improve their delivery efficiencies. In contrast, AAV2 does not perform better under the reverse transduction format. Interestingly, increased vector uptake by cells does not provide a complete explanation for the increased transduction efficiency. Our findings offer a simple and practical method for improving transduction outcomes in vitro in cell types less permissive to a particular AAV vector.

Application of Materials as Medical Devices with Localized Drug Delivery Capabilities for Enhanced Wound Repair.

The plentiful assortment of natural and synthetic materials can be leveraged to accommodate diverse wound types, as well as different stages of the healing process. An ideal material is envisioned to promote tissue repair with minimal inconvenience for patients. Traditional materials employed in the clinical setting often invoke secondary complications, such as infection, pain, foreign body reaction, and chronic inflammation. This review surveys the repertoire of surgical sutures, wound dressings, surgical glues, orthopedic fixation devices and bone fillers with drug eluting capabilities. It highlights the various techniques developed to effectively incorporate drugs into the selected material or blend of materials for both soft and hard tissue repair. The mechanical and chemical attributes of the resultant materials are also discussed, along with their biological outcomes in vitro and/or in vivo. Perspectives and challenges regarding future research endeavors are also delineated for next-generation wound repair materials.

Materials from Mussel-Inspired Chemistry for Cell and Tissue Engineering Applications.

Current advances in biomaterial fabrication techniques have broadened their application in different realms of biomedical engineering, spanning from drug delivery to tissue engineering. The success of biomaterials depends highly on the ability to modulate cell and tissue responses, including cell adhesion, as well as induction of repair and immune processes. Thus, most recent approaches in the field have concentrated on functionalizing biomaterials with different biomolecules intended to evoke cell- and tissue-specific reactions. Marine mussels produce mussel adhesive proteins (MAPs), which help them strongly attach to different surfaces, even under wet conditions in the ocean. Inspired by mussel adhesiveness, scientists discovered that dopamine undergoes self-polymerization at alkaline conditions. This reaction provides a universal coating for metals, polymers, and ceramics, regardless of their chemical and physical properties. Furthermore, this polymerized layer is enriched with catechol groups that enable immobilization of primary amine or thiol-based biomolecules via a simple dipping process. Herein, this review explores the versatile surface modification techniques that have recently been exploited in tissue engineering and summarizes polydopamine polymerization mechanisms, coating process parameters, and effects on substrate properties. A brief discussion of polydopamine-based reactions in the context of engineering various tissue types, including bone, blood vessels, cartilage, nerves, and muscle, is also provided.

Identification of Whole Mitochondrial Genomes from Venezuela and Implications on Regional Phylogenies in South America.

Recent studies have expanded and refined the founding haplogroups of the Americas using whole mitochondrial (mtDNA) genome analysis. In addition to pan-American lineages, specific variants have been identified in a number of studies that show higher frequencies in restricted geographical areas. To further characterize Native American maternal lineages and specifically examine local patterns within South America, we analyzed 12 maternally unrelated Yekuana whole mtDNA genomes from one village (Sharamaña) that include the four major Native American haplogroups A2, B2, C1, and D1. Based on our results, we propose a reconfiguration of one subhaplogroup A2 (A2aa) that is specific to South America and identify other singleton branches across the four haplogroups. Furthermore, we show nucleotide diversity values that increase from north to south for haplogroups C1 and D1. The results from our work add to the growing mitogenomic data that highlight local phylogenies and support the rapid genetic differentiation of South American populations, which has been correlated with the linguistic diversity in the region by previous studies.

The impact of pioglitazone on bladder cancer and cardiovascular events.

Type 2 diabetes mellitus (T2DM) is a chronic condition with increasing prevalence and severe complications. Thiazolidinediones have been marketed since 1997 and are effective glucose-lowering drugs, but individual drugs within the class have been linked to serious adverse effects that resulted in the removal of troglitazone from the market, restrictions to rosiglitazone's use, and a warning added to pioglitazone's label. In 2007, a meta-analysis linked rosiglitazone to myocardial infarction (MI). Pioglitazone does not appear to share this risk. To the contrary, pioglitazone may reduce risk for MI. However, retrospective evaluations have increasingly linked pioglitazone to a higher risk of bladder cancer that appears to be time- and dose-dependent. Pioglitazone remains a medication appropriate for consideration in the management of T2DM; however, clinicians and patients should weigh its risks compared with alternatives, with a regular review of risks.

The epidemiology of intermittent and chronic ataxia in children in Manitoba, Canada.

AIM: To determine the epidemiology of chronic ataxia in children in Manitoba, Canada. METHOD: A retrospective study using multiple sources and disease codes identified children (age 0-16y) with chronic ataxia (>2mo duration or recurrent episodes of ataxia) seen at Winnipeg Children's Hospital from 1991 to 2008. Patients with isolated peripheral nerve diseases, vestibular disorders, or brain tumors were excluded. RESULTS: We identified 184 patients (males=females; mean age 15y, SD 7y 8mo) with chronic ataxia. Median age at the presenting symptom onset was 1 year 3 months and at ataxia onset 3 years 1 month. Median duration of follow-up was 6 years 5 months. During the study period, the crude incidence rate was 5.77 in 10,000; the crude prevalence rate was 6.59 in 10,000; and the crude mortality rate 0.446 in 10,000. The most common presenting symptoms were developmental delay, ataxia, or seizures. The most common diagnoses (known in 129) were Angelman syndrome (n=16), ataxia telangiectasia (n=13), mitochondrial disease (n=9), Friedreich ataxia (n=7), stroke (n=7), and familial/genetic episodic ataxia (n=7). INTERPRETATION: Chronic ataxia is a relatively common early-presenting symptom in childhood. A specific diagnosis is possible in 70% of patients after extensive investigations. The mortality rate is relatively low and the disease burden is high with significant comorbidities including developmental delay and epilepsy.

Primary care family physicians' experiences with clinical integration in qualitative and mixed reviews: a systematic review protocol.

INTRODUCTION: Clinical (service) integration in primary care settings describes how comprehensive care is coordinated by family physicians (FPs) over time across healthcare contexts to meet patient care needs. To improve care integration and healthcare service planning, a systematic approach to understanding its numerous influencing factors is paramount. The objective of this study is to generate a comprehensive map of FP-perceived factors influencing clinical integration across diseases and patient demographics. METHODS AND ANALYSIS: We developed the protocol with the guidance of the Joanna Briggs Institute systematic review methodology framework. An information specialist built search strategies for MEDLINE, EMBASE and CINAHL databases using keywords and MeSH terms iteratively collected from a multidisciplinary team. Two reviewers will work independently throughout the study process, from article selection to data analysis. The identified records will be screened by title and abstract and reviewed in the full text against the criteria: FP in primary care (population), clinical integration (concept) and qualitative and mixed reviews published in 2011-2021 (context). We will first describe the characteristics of the review studies. Then, we will extract qualitative, FP-perceived factors and group them by content similarities, such as patient factors. Lastly, we will describe the types of extracted factors using a custom framework. ETHICS AND DISSEMINATION: Ethics approval is not required for a systematic review. The identified factors will help generate an item bank for a survey that will be developed in the Phase II study to ascertain high-impact factors for intervention(s), as well as evidence gaps to guide future research. We will share the study findings with various knowledge users to promote awareness of clinical integration issues through multiple channels: publications and conferences for researchers and care providers, an executive summary for clinical leaders and policy-makers, and social media for the public.

COSMOS: a platform for real-time morphology-based, label-free cell sorting using deep learning.

Cells are the singular building blocks of life, and a comprehensive understanding of morphology, among other properties, is crucial to the assessment of underlying heterogeneity. We developed Computational Sorting and Mapping of Single Cells (COSMOS), a platform based on Artificial Intelligence (AI) and microfluidics to characterize and sort single cells based on real-time deep learning interpretation of high-resolution brightfield images. Supervised deep learning models were applied to characterize and sort cell lines and dissociated primary tissue based on high-dimensional embedding vectors of morphology without the need for biomarker labels and stains/dyes. We demonstrate COSMOS capabilities with multiple human cell lines and tissue samples. These early results suggest that our neural networks embedding space can capture and recapitulate deep visual characteristics and can be used to efficiently purify unlabeled viable cells with desired morphological traits. Our approach resolves a technical gap in the ability to perform real-time deep learning assessment and sorting of cells based on high-resolution brightfield images.

Emerging genetic patterns of the European Neolithic: perspectives from a late Neolithic Bell Beaker burial site in Germany.

The transition from hunting and gathering to agriculture in Europe is associated with demographic changes that may have shifted the human gene pool of the region as a result of an influx of Neolithic farmers from the Near East. However, the genetic composition of populations after the earliest Neolithic, when a diverse mosaic of societies that had been fully engaged in agriculture for some time appeared in central Europe, is poorly known. At this period during the Late Neolithic (ca. 2,800-2,000 BC), regionally distinctive burial patterns associated with two different cultural groups emerge, Bell Beaker and Corded Ware, and may reflect differences in how these societies were organized. Ancient DNA analyses of human remains from the Late Neolithic Bell Beaker site of Kromsdorf, Germany showed distinct mitochondrial haplotypes for six individuals, which were classified under the haplogroups I1, K1, T1, U2, U5, and W5, and two males were identified as belonging to the Y haplogroup R1b. In contrast to other Late Neolithic societies in Europe emphasizing maintenance of biological relatedness in mortuary contexts, the diversity of maternal haplotypes evident at Kromsdorf suggests that burial practices of Bell Beaker communities operated outside of social norms based on shared maternal lineages. Furthermore, our data, along with those from previous studies, indicate that modern U5-lineages may have received little, if any, contribution from the Mesolithic or Neolithic mitochondrial gene pool.

Desensitization treatment for hypersensitivity reaction to octreotide in an acromegalic patient.

Octreotide is widely used as medical therapy for acromegaly. It is known to markedly reduce growth hormone levels, improve symptoms and reduce tumor size. Common side effects include gastrointestinal symptoms, hepatobiliary disorders, dizziness, headaches, bradycardia, hyperglycemia or hypoglycemia and thyroid dysfunction. Although urticaria, allergy/hypersensitivity reactions and anaphylaxis have been noted as possible adverse reactions, there is a lack of data showing a causal relationship between octreotide and hypersensitivity reactions and there is no information on management when continued use of this medication is essential. We now report a case of a 60 year old male with acromegaly who had presented with a cutaneous hypersensitivity reaction to octreotide. In addition he failed treatment with surgery, radiation, and dopamine agonist and could no longer afford to continue treatment with pegvisomant. The patient underwent desensitization treatment for his octreotide allergy and was able to resume treatment without any further side effects. We believe this case represents the first report of successful desensitization treatment for octreotide allergy in an acromegalic patient.

Residual CIS after neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer: Implications for neoadjuvant trials.

PURPOSE: To better define surrogate endpoints for neoadjuvant chemotherapy (NAC) trials in patients with muscle-invasive bladder cancer. We compared survival in patients with carcinoma in-situ (CIS) only vs. complete response following NAC and radical cystectomy (RC). MATERIALS AND METHODS: Patients with cT2-4N0M0 disease treated with NAC and RC between 2001 and 2018 were stratified by response: complete response (CR, pT0N0), partial response (PR, pTaN0, pT1N0+/-CIS), CIS-only (pTisN0), stable disease (SD, pT2N0), or progressive disease (PD, >pT2N0). Primary endpoints were overall survival (OS) and risk of recurrence in patients with CIS-only vs. CR. Multivariable Cox proportional hazards regression model was used for OS and a competing risks proportional hazards model was used for risk of recurrence. RESULTS: Of 1,406 patients in our institution cohort, 340 patients met inclusion criteria. Kaplan-Meier mean estimates of OS for CR and CIS-only were 108.9 months (95% CI 89.7-127.9) and 125.8 months (95% CI 112.3-139.3), respectively (P = 0.13). Cox proportional hazards model found no difference in OS between patients with PR (HR 1.06, 95% CI 0.33-2.58, P = 0.897) or CIS-only (HR 0.422, 95% CI 0.15-1.18, P = 0.101) when compared to CR. The risk of recurrence was similar between patients with CIS-only (HR 0.73, 95% 0.29-1.84, P = 0.49) and PR (HR 1.32, 95% CI 0.54-3.29, P = 0.54) when compared to CR on competing risks analysis. CONCLUSIONS: Residual CIS-only after NAC and RC demonstrated similar survival outcomes when compared to patients with pathologic CR. Further study in large multi-institutional cohorts may further validate CIS-only as an additional surrogate endpoint after NAC and may inform future trials.

Hospitalized patients with 2009 pandemic influenza A (H1N1) virus infection in the United States--September-October 2009.

Given the potential worsening clinical severity of 2009 pandemic influenza A (H1N1) virus (pH1N1) infection from spring to fall 2009, we conducted a clinical case series among patients hospitalized with pH1N1 infection from September through October 2009. A case patient was defined as a hospitalized person who had test results positive for pH1N1 virus by real-time reverse-transcription polymerase chain reaction. Among 255 hospitalized patients, 34% were admitted to an intensive care unit and 8% died. Thirty-four percent of patients were children <18 years of age, 8% were adults ≥ 65 years of age, and 67% had an underlying medical condition. Chest radiographs obtained at hospital admission that had findings that were consistent with pneumonia were noted in 103 (46%) of 255 patients. Among 255 hospitalized patients, 208 (82%) received neuraminidase inhibitors, but only 47% had treatment started ≤ 2 days after illness onset. Overall, characteristics of hospitalized patients with pH1N1 infection in fall 2009 were similar to characteristics of patients hospitalized with pH1N1 infection in spring 2009, which suggests that clinical severity did not change substantially over this period.

Characterization of population structure from the mitochondrial DNA vis-à-vis language and geography in Papua New Guinea.

Situated along a corridor linking the Asian continent with the outer islands of the Pacific, Papua New Guinea has long played a key role in understanding the initial peopling of Oceania. The vast diversity in languages and unique geographical environments in the region have been central to the debates on human migration and the degree of interaction between the Pleistocene settlers and newer migrants. To better understand the role of Papua New Guinea in shaping the region's prehistory, we sequenced the mitochondrial DNA (mtDNA) control region of three populations, a total of 94 individuals, located in the East Sepik Province of Papua New Guinea. We analyzed these samples with a large data set of Oceania populations to examine the role of geography and language in shaping population structure within New Guinea and between the region and Island Melanesia. Our results from median-joining networks, star-cluster age estimates, and population genetic analyses show that while highland New Guinea populations seem to be the oldest settlers, there has been significant gene flow within New Guinea with little influence from geography or language. The highest genetic division is between Papuan speakers of New Guinea versus East Papuan speakers located outside of mainland New Guinea. Our study supports the weak language barriers to genetic structuring among populations in close contact and highlights the complexity of understanding the genetic histories of Papua New Guinea in association with language and geography.

Adeno-Associated Virus (AAV) Vectors: Rational Design Strategies for Capsid Engineering.

Adeno-associated virus (AAV) consists of a simple genome, infects mammalian cells, displays nonpathogenicity in humans, and spans an array of serotypes and variants bearing distinct tissue tropisms. These attributes lend AAV tremendous promise as a gene delivery vector, further substantiated by its extensive testing in human clinical trials. Rational design approaches to capsid engineering leverage current scientific knowledge of AAV to further modulate, enhance and optimize the performance of the vectors. Capsid modification strategies include amino acid point mutations, peptide domain insertions, and chemical biology approaches. Through such efforts, insights regarding AAV capsid sequence-structure-function relationships can be learned. Developments over the last 5 years in rational design-based capsid engineering approaches will be presented and discussed.

Honing Cell and Tissue Culture Conditions for Bone and Cartilage Tissue Engineering.

An avenue of tremendous interest and need in health care encompasses the regeneration of bone and cartilage. Over the years, numerous tissue engineering strategies have contributed substantial progress toward the realization of clinically relevant therapies. Cell and tissue culture protocols, however, show many variations that make experimental results among different publications challenging to compare. This collection surveys prevalent cell sources, soluble factors, culture medium formulations, environmental factors, and genetic modification approaches in the literature. The intent of consolidating this information is to provide a starting resource for scientists considering how to optimize the parameters for cell differentiation and tissue culture procedures within the context of bone and cartilage tissue engineering.

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect.

Reconstruction of large bone defects can be complicated by the presence of both infection and local antibiotic administration. This can be addressed through a two-stage reconstructive approach, called the Masquelet technique, that involves the generation of an induced osteogenic membrane over a temporary poly(methyl methacrylate) (PMMA) space maintainer, followed by definitive reconstruction after the induced membrane is formed. Given that infection and antibiotic delivery each have independent effects on local tissue response, the objective of this study is to evaluate the interaction between local clindamycin release and bacterial contamination with regards to infection prevention and the restoration of pro-osteogenic gene expression in the induced membrane. Porous PMMA space maintainers with or without clindamycin were implanted in an 8 mm rat femoral defect model with or without Staphylococcus aureus inoculation for 28 days in a full-factorial study design (four groups, n = 8/group). Culture results demonstrated that 8/8 animals in the inoculated/no antibiotic group were infected at 4 weeks, which was significantly reduced to 1/8 animals in the inoculated/antibiotic group. Quantitative polymerase chain reaction analysis demonstrated that clindamycin treatment restores inflammatory cytokine and growth factor expression to the same levels as the no inoculation/no antibiotic group, demonstrating that clindamycin can ameliorate the negative effects of bacterial inoculation and does not itself negatively impact the expression of important cytokines. Main effect analysis shows that bacterial inoculation and clindamycin treatment have independent and interacting effects on the gene expression profile of the induced membrane, further highlighting that antibiotics play an important role in the regeneration of infected defects apart from their antimicrobial properties.

Evaluation of Gelatin Microparticles as Adherent-Substrates for Mesenchymal Stem Cells in a Hydrogel Composite.

Due to the lack of cell-adhesive moieties in traditional synthetic hydrogels, the present work investigated the use of degradable gelatin microparticles (GMPs) as temporary adherent substrates for anchorage-dependent mesenchymal stem cells (MSCs). MSCs were seeded onto GMPs of varying crosslinking densities and sizes to investigate their role on influencing MSC differentiation and aggregation. The MSC-seeded GMPs were then encapsulated in poly(ethylene glycol)-based hydrogels and cultured in serum-free, growth factor-free osteochondral medium. Non-seeded MSCs co-encapsulated with GMPs in the hydrogels were used as a control for comparison. Over the course of 35 days, MSCs seeded on GMPs exhibited more cell-cell contacts, greater chondrogenic potential, and a down-regulation of osteogenic markers compared to the controls. Although the factors of GMP crosslinking and size had nominal influence on MSC differentiation and aggregation, GMPs demonstrate potential as an adherent-substrate for improving cell delivery from hydrogel scaffolds by facilitating cell-cell contacts and improving MSC differentiation.