Renal transplant recipients undergoing endovascular abdominal aortic aneurysm repair have increased risk of perioperative acute kidney injury but no difference in late mortality.

OBJECTIVE: Renal transplant is associated with substantial survival advantage in patients with end-stage renal disease. However, little is known about the outcomes of renal transplant recipients (RTRs) after endovascular abdominal aortic aneurysm repair (EVAR). This study aimed to study the effect of renal transplant on perioperative outcomes and long-term survival after elective infrarenal EVAR. METHODS: The Vascular Quality Initiative database was queried for all patients undergoing elective EVAR from 2003 to 2021. Functioning RTRs were compared with non-renal transplant recipients without a diagnosis of end-stage renal disease (non-RTRs). The outcomes included 30-day mortality, acute kidney injury (AKI), new renal failure requiring renal replacement therapy (RRT), endoleak, aortic-related reintervention, major adverse cardiac events, and 5-year survival. A logistic regression analysis was used to assess the association between RTRs and perioperative outcomes. RESULTS: Of 60,522 patients undergoing elective EVAR, 180 (0.3%) were RTRs. RTRs were younger (median, 71 years vs 74.5 years; P < .001), with higher incidence of hypertension (92% vs 84%; P = .004) and diabetes (29% vs 21%; P = .005). RTRs had higher median preoperative serum creatinine (1.3 mg/dL vs 1.0 mg/dL; P < .001) and lower estimated glomerular filtration rate (51.6 mL/min vs 69.4 mL/min; P < .001). There was no difference in the abdominal aortic aneurysm diameter and incidence of concurrent iliac aneurysms. Procedurally, RTRs were more likely to undergo general anesthesia with lower amount of contrast used (median, 68.6 mL vs 94.8 ml; P < .001) and higher crystalloid infusion (median, 1700 mL vs 1500 mL; P = .039), but no difference was observed in the incidence of open conversion, endoleak, operative time, and blood loss. Postoperatively, RTRs experienced a higher rate of AKI (9.4% vs 2.7%; P < .001), but the need for new RRT was similar (1.1% vs 0.4%; P = .15). There was no difference in the rates of postoperative mortality, aortic-related reintervention, and major adverse cardiac events. After adjustment for potential confounders, RTRs remained associated with increased odds of postoperative AKI (odds ratio, 3.33; 95% confidence interval, 1.93-5.76; P < .001) but had no association with other postoperative complications. A subgroup analysis identified that diabetes (odds ratio, 4.21; 95% confidence interval, 1.17-15.14; P = .02) is associated with increased odds of postoperative AKI among RTRs. At 5 years, the overall survival rates were similar (83.4% vs 80%; log-rank P = .235). CONCLUSIONS: Among patients undergoing elective infrarenal EVAR, RTRs were independently associated with increased odds of postoperative AKI, without increased postoperative renal failure requiring RRT, mortality, endoleak, aortic-related reintervention, or major adverse cardiac events. Furthermore, 5-year survival was similar. As such, while EVAR may confer comparable benefits and technical success perioperatively, RTRs should have aggressive and maximally optimized renal protection to mitigate the risk of postoperative AKI.

Prophylactic sac outflow vessel embolization is associated with improved sac regression in patients undergoing endovascular aortic aneurysm repair.

OBJECTIVE: Type II endoleaks (T2Es), often identified after endovascular aneurysm repair (EVAR), have been associated with late endograft failure and secondary rupture. The number and size of the patent aortic aneurysm sac outflow vessels (ie, the inferior mesenteric, lumbar, and accessory renal arteries) have been implicated as known risk factors for persistent T2Es. Given the technical challenges associated with post-EVAR embolization, prophylactic embolization of aortic aneurysm sac outflow vessels has been advocated to prevent T2Es; however, the evidence available at present is limited. We sought to examine the effects of concomitant prophylactic aortic aneurysm sac outflow vessel embolization in patients undergoing EVAR. METHODS: Patients aged ≥18 years included in the Society for Vascular Surgery Vascular Quality Initiative database who had undergone elective EVAR for intact aneurysms between January 2009 and November 2020 were included in the present study. Patients with a history of prior aortic repair and those without available follow-up data were excluded. The patient demographics, operative characteristics, and outcomes were analyzed by group: EVAR alone vs EVAR with prophylactic sac outflow vessel embolization (emboEVAR). The outcomes of interest were the in-hospital postoperative complication rates, incidence of aneurysmal sac regression (≥5 mm) and T2Es, and reintervention rates during follow-up. RESULTS: A total of 15,060 patients were included. Of these patients, 272 had undergone emboEVAR and 14,788 had undergone EVAR alone. No significant differences were found between the two groups in age, comorbidities, or anatomic characteristics, including the mean maximum preoperative aortic diameter (5.5 vs 5.6 cm; P = .48). emboEVAR was associated with significantly longer procedural times (148 vs 124 minutes; P < .0001), prolonged fluoroscopy times (32 vs 23 minutes; P < .0001), increased contrast use (105 vs 91 mL; P < .0001), without a significant reduction in T2Es at case completion (17.7% vs 16.3%; P = .54). The incidence of postoperative complications (3.7% vs 4.6%; P = .56), index hospitalization reintervention rates (0.7% vs 1.3%; P = .59), length of stay (1.8 vs 2 days; P = .75), and 30-day mortality (0% vs 0%; P = 1.00) were similar between the two groups. At mid-term follow-up (14.6 ± 6.2 months), the emboEVAR group had a significantly greater mean reduction in the maximum aortic diameter (0.69 vs 0.54 cm; P = .006), with a greater proportion experiencing sac regression of ≥5 mm (53.5% vs 48.7%). The reintervention rates were similar between the two groups. On multivariable analysis, prophylactic aortic aneurysm sac outflow vessel embolization (odds ratio, 1.34; 95% confidence interval, 1.04-1.74; P = .024) was a significant independent predictor of sac regression. CONCLUSIONS: Prophylactic sac outflow vessel embolization can be performed safely for patients with intact aortic aneurysms undergoing elective EVAR without significant associated perioperative morbidity or mortality. emboEVAR was associated with significant sac regression compared with EVAR alone at mid-term follow-up. Although no decrease was found in the incidence of T2Es, this technique shows promise, and future efforts should focus on identifying a subset of aneurysm and outflow branch characteristics that will benefit from concomitant selective vs complete prophylactic sac outflow vessel embolization.

Practice patterns and outcomes for pediatric ANCA vasculitis transplant recipients in a national cohort.

BACKGROUND: Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a rare condition in pediatric patients. Little is known about practice patterns and outcomes of pediatric transplant patients. The purpose of our study was to examine differences in patient characteristics, immunosuppression, and long-term graft outcomes between ANCA and non-ANCA vasculitis recipients. METHODS: We used the Scientific Registry of Transplant Recipients to evaluate pediatric ANCA vasculitis recipients between the ages of 1 and 22 years old from 1991 to 2017 and compared them to non-ANCA vasculitis patients during the same time cohort in the USA. RESULTS: A total of 26,431 transplant recipients were identified, of these, 337 with ANCA vasculitis. Mean 1-year eGFR was 62.46 and 64.92 ml/min/1.73 m2 (p = 0.002), and mean 5-year eGFR was 57.95 and 59.38 ml/min/1.73 m2 (p = 0.18) between the non-ANCA and ANCA groups, respectively. Five-year graft survival was similar in both groups (non-ANCA 75.5 vs. ANCA 78.6%; p = 0.19). Of those with graft loss within the ANCA group, only 0.6% was secondary to disease recurrence (p = 0.14). CONCLUSIONS: Kidney transplant is a safe treatment modality for children with ANCA-related kidney failure. ANCA patients have comparable graft survival when compared to the general transplant population with a low risk of recurrence. Thymoglobulin was used in a higher proportion within the ANCA group compared to the non-ANCA group. Tacrolimus, mycophenolate mofetil/mycophenolic acid, and steroids were the predominant maintenance immunosuppression used in both groups. A higher resolution version of the Graphical abstract is available as Supplementary information.

Disparate access to breast cancer screening and treatment.

BACKGROUND: Barriers to breast cancer screening remain despite Medicaid expansion for preventive screening tests and implementation of patient navigation programs under the Affordable Care Act. Women from underserved communities experience disproportionately low rates of screening mammography. This study compares barriers to breast cancer screening among women at an inner-city safety-net center (City) and those at a suburban county medical center (County). Inner city and suburban county medical centers' initiatives were studied to compare outcomes of breast cancer screening and factors that influence access to care. METHODS: Women 40 years of age or older delinquent in breast cancer screening were offered patient navigation services between October 2014 and September 2019. Four different screening time-to-event intervals were investigated: time from patient navigation acceptance to screening mammography, to diagnostic mammography, to biopsy, and overall screening completion time. Barriers to complete breast cancer screening between the two centers were compared. RESULTS: Women from lowest income quartiles took significantly longer to complete breast cancer screening when compared to women from higher income quartiles when a barrier was present, regardless of barrier type and center. Transportation was a major barrier to screening mammography completion, while fear was the major barrier to abnormal screening work up. CONCLUSION: Disparity in breast cancer screening and management persists despite implementation of a patient navigation program. In the presence of a barrier, women from the lowest income quartiles have prolonged breast cancer screening completion time regardless of center or barrier type. Women who experience fear have longest screening time completion. Future directions aim to increase resource allocation to ameliorate wait times in overburdened safety-net hospitals as well as advanced training for patient navigators to alleviate women's fears.

Metal ions and graphene-based compounds as alternative treatment options for burn wounds infected by antibiotic-resistant Pseudomonas aeruginosa.

Burn infections caused by Pseudomonas aeruginosa pose a major complication in wound healing. This study aimed to determine the antimicrobial effect of metal ions, graphene (Gr), and graphene oxide (GO), individually and in combination, against the planktonic and biofilm states of two antimicrobially resistant clinical strains of P. aeruginosa each with different antibiotic resistance profiles. Minimum inhibitory, minimum bactericidal, and fractional inhibitory concentrations were performed to determine the efficacy of the metal ions and graphene composites individually and their synergy in combination. Crystal violet biofilm and XTT assays measured the biofilm inhibition and metabolic activity, respectively. Molybdenum, platinum, tin, gold, and palladium ions exhibited the greatest antimicrobial activity (MIC = 7.8-26.0 mg/L), whilst GO and Gr demonstrated moderate-to-no effect against the planktonic bacterial cells, irrespective of their antibiograms. Biofilms were inhibited by zinc, palladium, silver, and graphene. In combination, silver-graphene and molybdenum-graphene inhibited both the planktonic and biofilm forms of the bacteria making them potential candidates for development into topical antimicrobials for burns patients infected with antibiotic-resistant P. aeruginosa.

Functional analysis of the Helicobacter pullorum N-linked protein glycosylation system.

N-linked protein glycosylation systems operate in species from all three domains of life. The model bacterial N-linked glycosylation system from Campylobacter jejuni is encoded by pgl genes present at a single chromosomal locus. This gene cluster includes the pglB oligosaccharyltransferase responsible for transfer of glycan from lipid carrier to protein. Although all genomes from species of the Campylobacter genus contain a pgl locus, among the related Helicobacter genus only three evolutionarily related species (H. pullorum, H. canadensis and H. winghamensis) potentially encode N-linked protein glycosylation systems. Helicobacter putative pgl genes are scattered in five chromosomal loci and include two putative oligosaccharyltransferase-encoding pglB genes per genome. We have previously demonstrated the in vitro N-linked glycosylation activity of H. pullorum resulting in transfer of a pentasaccharide to a peptide at asparagine within the sequon (D/E)XNXS/T. In this study, we identified the first H. pullorum N-linked glycoprotein, termed HgpA. Production of histidine-tagged HgpA in the background of insertional knockout mutants of H. pullorum pgl/wbp genes followed by analysis of HgpA glycan structures demonstrated the role of individual gene products in the PglB1-dependent N-linked protein glycosylation pathway. Glycopeptide purification by zwitterionic-hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry identified six glycosites from five H. pullorum proteins, which was consistent with proteins reactive with a polyclonal antiserum generated against glycosylated HgpA. This study demonstrates functioning of a H. pullorum N-linked general protein glycosylation system.

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ3N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli.

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ3N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ3N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ3N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ3N)]Br.

Chromosomal integration vectors allowing flexible expression of foreign genes in Campylobacter jejuni.

BACKGROUND: Campylobacter jejuni is a major cause of human gastroenteritis yet there is limited knowledge of how disease is caused. Molecular genetic approaches are vital for research into the virulence mechanisms of this important pathogen. Vectors that allow expression of genes in C. jejuni via recombination onto the chromosome are particularly useful for genetic complementation of insertional knockout mutants and more generally for expression of genes in particular C. jejuni host backgrounds. METHODS: A series of three vectors that allow integration of genes onto the C. jejuni chromosome were constructed by standard cloning techniques with expression driven from three different strong promoters. Following integration onto the C. jejuni chromosome expression levels were quantified by fluorescence measurements and cells visualized by fluorescence microscopy. RESULTS: We have created plasmid, pCJC1, designed for recombination-mediated delivery of genes onto the C. jejuni chromosome. This plasmid contains a chloramphenicol resistance cassette (cat) with upstream and downstream restriction sites, flanked by regions of the C. jejuni pseudogene Cj0223. Cloning of genes immediately upstream or downstream of the cat gene allows their subsequent introduction onto the C. jejuni chromosome within the pseudogene. Gene expression can be driven from the native gene promoter if included, or alternatively from the cat promoter if the gene is cloned downstream of, and in the same transcriptional orientation as cat. To provide increased and variable expression of genes from the C. jejuni chromosome we modified pCJC1 through incorporation of three relatively strong promoters from the porA, ureI and flaA genes of C. jejuni, Helicobacter pylori and Helicobacter pullorum respectively. These promoters along with their associated ribosome binding sites were cloned upstream of the cat gene on pCJC1 to create plasmids pCJC2, pCJC3 and pCJC4. To test their effectiveness, a green fluorescent protein (gfp) reporter gene was inserted downstream of each of the three promoters and following integration of promoter-gene fusions onto the C. jejuni host chromosome, expression levels were quantified. Expression from the porA promoter produced the highest fluorescence, from flaA intermediate levels and from ureI the lowest. Expression of gfp from the porA promoter enabled visualization by fluorescent microscopy of intracellular C. jejuni cells following invasion of HeLa cells. CONCLUSIONS: The plasmids constructed allow stable chromosomal expression of genes in C. jejuni and, depending on the promoter used, different expression levels were obtained making these plasmids useful tools for genetic complementation and high level expression.

A novel combination approach to effectively reduce inflammation and neurodegeneration in multiple sclerosis models.

Multiple sclerosis (MS) is an autoimmune disease characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. Unfortunately, there is no cure for it. Current therapies that target immunomodulation and/or immunosuppression show only modest beneficial effects, have many side effects, and do not block neurodegeneration or progression of the disease. Since neurodegeneration and in particular axonal degeneration is implicated in disability in progressive MS, development of novel therapeutic strategies to attenuate the neurodegenerative processes is imperative. This study aims to develop new safe and efficacious treatments that address both the inflammatory and neurodegenerative aspects of MS using its animal model, experimental allergic encephalomyelitis (EAE). In EAE, the cysteine protease calpain is upregulated in CNS tissue, and its activity correlates with neurodegeneration. Our immunologic studies on MS have indicated that increased calpain activity promotes pro-inflammatory T helper (Th)1 cells and the severity of the disease in EAE, suggesting that calpain inhibition could be a novel target to combat neurodegeneration in MS/EAE. While calpain inhibition by SNJ1945 reduced disease severity, treatment of EAE animals with a novel protease-resistant altered small peptide ligand (3aza-APL) that mimic myelin basic protein (MBP), also decreased the incidence of EAE, disease severity, infiltration of inflammatory cells, and protected myelin. A reduction in inflammatory T-cells with an increase in Tregs and myeloid suppressor cells is also found in EAE mice treated with SNJ1945 and 3aza-APL. Thus, a novel combination strategy was tested in chronic EAE mouse model in B10 mice which showed multiple pathological mechanisms could be addressed by simultaneous treatment with calpain inhibitor SNJ1945 and protease-resistant 3aza-APL to achieve a stronger therapeutic effect.

Guidelines for the assessment of the impacted maxillary canine.

UNLABELLED: Canine impactions are frequently encountered, occurring in 1.7% of the population. The aim of this paper is to provide guidance on the assessment and management of cases which present in general dental practice. Canine position is considered in four categories; canine overlap with adjacent incisor, vertical canine height, angulation to midline and position of canine root apex. Good, average and poor prognostic outcomes are considered for each category and a brief outline of their management is included. CLINICAL RELEVANCE: Canine impactions frequently present during routine examination. Appropriate recognition, investigation and referral, if necessary, are paramount to successful treatment.

Perspectives of COVID-19 vaccine-hesitant emergency department patients to inform messaging platforms to promote vaccine uptake.

OBJECTIVES: Efforts to promote COVID-19 vaccine acceptance must consider the critical role of the emergency department (ED) in providing health care to underserved patients. Focusing on patients who lacked primary care, we sought to elicit the perspectives of unvaccinated ED patients regarding COVID-19 vaccination concerns and potential approaches that might increase their vaccine acceptance. METHODS: We conducted this qualitative interview study from August to November 2021 at four urban EDs in San Francisco, California; Seattle, Washington; Durham, North Carolina; and Philadelphia, Pennsylvania. We included ED patients who were ≥18 years old, fluent in English or Spanish, had not received a COVID-19 vaccine, and did not have primary care physicians or clinics. We excluded patients who were unable to complete an interview, in police custody, under suspicion of active COVID-19 illness, or presented with a psychiatric chief complaint. We enrolled until we reached thematic saturation in relevant domains. We analyzed interview transcripts with a content analysis approach focused on identifying concerns about COVID-19 vaccines and ideas regarding the promotion of vaccine acceptance and potential trusted messengers. RESULTS: Of 65 patients enrolled, 28 (43%) identified as female, their median age was 36 years (interquartile range 29-49), and 12 (18%) interviews were conducted in Spanish. Primary concerns about COVID-19 vaccines included risk of complications, known and unknown side effects, and fear of contracting COVID-19 from vaccines. Trust played a major role for patients in deciding which sources to use for vaccine information and in engendering vaccine acceptance. Health care providers and family or friends were commonly cited as trusted messengers of information. CONCLUSIONS: We characterized concerns about COVID-19 vaccines, uncovered themes that may promote vaccine acceptance, and identified trusted messengers-primarily health care professionals. These data may inform the development of nuanced COVID-19 vaccine messaging platforms to address COVID-19 vaccine hesitancy among underserved ED populations.

Characterization of the structurally diverse N-linked glycans of Campylobacter species.

The Gram-negative bacterium Campylobacter jejuni encodes an extensively characterized N-linked protein glycosylation system that modifies many surface proteins with a heptasaccharide glycan. In C. jejuni, the genes that encode the enzymes required for glycan biosynthesis and transfer to protein are located at a single pgl gene locus. Similar loci are also present in the genome sequences of all other Campylobacter species, although variations in gene content and organization are evident. In this study, we have demonstrated that only Campylobacter species closely related to C. jejuni produce glycoproteins that interact with both a C. jejuni N-linked-glycan-specific antiserum and a lectin known to bind to the C. jejuni N-linked glycan. In order to further investigate the structure of Campylobacter N-linked glycans, we employed an in vitro peptide glycosylation assay combined with mass spectrometry to demonstrate that Campylobacter species produce a range of structurally distinct N-linked glycans with variations in the number of sugar residues (penta-, hexa-, and heptasaccharides), the presence of branching sugars, and monosaccharide content. These data considerably expand our knowledge of bacterial N-linked glycan structure and provide a framework for investigating the role of glycosyltransferases and sugar biosynthesis enzymes in glycoprotein biosynthesis with practical implications for synthetic biology and glycoengineering.

DNA sequence and analysis of human chromosome 8.

The International Human Genome Sequencing Consortium (IHGSC) recently completed a sequence of the human genome. As part of this project, we have focused on chromosome 8. Although some chromosomes exhibit extreme characteristics in terms of length, gene content, repeat content and fraction segmentally duplicated, chromosome 8 is distinctly typical in character, being very close to the genome median in each of these aspects. This work describes a finished sequence and gene catalogue for the chromosome, which represents just over 5% of the euchromatic human genome. A unique feature of the chromosome is a vast region of approximately 15 megabases on distal 8p that appears to have a strikingly high mutation rate, which has accelerated in the hominids relative to other sequenced mammals. This fast-evolving region contains a number of genes related to innate immunity and the nervous system, including loci that appear to be under positive selection--these include the major defensin (DEF) gene cluster and MCPH1, a gene that may have contributed to the evolution of expanded brain size in the great apes. The data from chromosome 8 should allow a better understanding of both normal and disease biology and genome evolution.

DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

Analysis of the DNA sequence and duplication history of human chromosome 15.

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

Ruthenium Metallotherapeutics: Novel Approaches to Combatting Parasitic Infections.

Human parasitic infections cause a combined global mortality rate of over one million people per annum and represent some of the most challenging diseases for medical intervention. Current chemotherapeutic strategies often require prolonged treatment, coupled with subsequent drug-induced cytotoxic morbidity to the host, while resistance generation is also a major concern. Metals have been used extensively throughout the history of medicine, with more recent applications as anticancer and antimicrobial agents. Ruthenium metallotherapeutic antiparasitic agents are highly effective at targeting a range of key parasites, including the causative agents of malaria, trypanosomiasis, leishmaniasis, amoebiasis, toxoplasmosis and other orphan diseases, while demonstrating lower cytotoxicity profiles than current treatment strategies. Generally, such compounds also demonstrate activity against multiple cellular target sites within parasites, including inhibition of enzyme function, cell membrane perturbation, and alterations to metabolic pathways, therefore reducing the opportunity for resistance generation. This review provides a comprehensive and subjective analysis of the rapidly developing area of ruthenium metal- based antiparasitic chemotherapeutics, in the context of rational drug design and potential clinical approaches to combatting human parasitic infections.

Pelvic fractures in severely injured elderly: a double-adjustment propensity score matched analysis from a level I trauma center.

PURPOSE: Pelvic trauma has increased risk of mortality in the elderly. Our study aimed to analyze the impact of the additional burden of pelvic fractures in severely injured elderly. METHODS: This is a retrospective analysis of a prospectively maintained trauma registry from 2012 to 2018 at an American College of Surgeons (ACS) verified Level I Trauma Center. Trauma patients aged ≥ 65 years with ISS ≥ 16 and AIS severity score ≥ 3 in at least two body regions were divided in two groups: group I, consisted of elderly polytrauma patients without pelvic fractures, and group II elderly who had concomitant pelvic fractures. We used a double-adjustment method using propensity score matching (PSM) with subsequent covariate adjustment to minimize the effect of confounding factors, and give unbiased estimation of the impact of pelvic fractures. Balance assessment was conducted by computing absolute standardized mean differences (ASMDs) and ASMD < 0.10 reflects good balance between groups. RESULTS: Of 12,774 patients admitted during this time, 411 (3.2%) elderly with a mean age of 77.75 ± 8.32 years met the inclusion criteria. Of this cohort, only 92 patients (22.4%) had pelvic fractures. Females outnumbered males (55 vs. 45%). Comparing characteristics of group I and group II using ASMDs, pelvic trauma patients were more likely to have higher systolic blood pressure (SBP), head injuries, lower extremity injuries, anticoagulant therapy, and cirrhosis. Fewer variables differed significantly after matching. We observed few instances of worse outcomes associated with pelvic trauma using PSM with and without covariate adjustment. Crude PSM without covariate adjustment, showed a significantly higher rate of deep vein thrombosis (DVT) for pelvic trauma (p < 0.001). Crude PSM also showed a significantly higher rate of ventilator-associated pneumonia (VAP) in group II (p = 0.006). PSM with covariate adjustment did not confirm differences on these outcomes. PSM both without and with covariate adjustment found lower ventilator days and ICU length of stay among patients with pelvic trauma. No significant differences were seen on 12 outcomes: death, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), cardiac arrest with cardiopulmonary resuscitation (CPR), myocardial infarction (MI), pulmonary embolism (PE), unplanned intubation, unplanned admission to intensive care unit (ICU), catheter-associated urinary tract infection (CAUTI), and hospital length of stay. CONCLUSIONS: At a Level I Trauma Center the additional burden of pelvic fractures in seriously injured elderly did not translate into higher mortality. PSM without covariate adjustment suggests worse rates among pelvic trauma patients for DVT and VAP but covariate adjustment removed statistical significance for both outcomes. Pelvic trauma patients had shorter time on ventilator and in the ICU. Whether similar analytic methods applied to patients from larger data sources would produce similar findings remains to be seen.

Improving Liver Transplant Outcomes for Hepatitis C Virus Hepatocellular Carcinoma in the Direct-Acting Antiviral Therapy Era.

BACKGROUND: Direct-acting antiviral (DAA) therapy has transformed the outcomes of liver transplant (LT) with hepatitis C virus (HCV). This study aimed to analyze the effects of DAA treatment for HCV-associated hepatocellular carcinoma (HCC) in LT. METHODS: We included patients confirmed with HCC on explant, analyzed data from United Network for Organ Sharing, and defined the pre-DAA era (2012-2013) and DAA era (2014-2016). RESULTS: HCV-associated HCC cases totaled 4778 (62%) during the study period. In the DAA era, the median recipient age was older and the median days on the waiting list were longer. For the donor, median age, body mass index, and the rate of HCV significantly increased in the DAA era. In pathology, the median largest tumor size was significantly higher; however, the rate of completed tumor necrosis was significant higher in the DAA era. The 3-year graft/patient survival had significantly improved in the DAA era. In multivariable analysis, the DAA era (hazard ratio, 0.79; 95% confidence interval, 0.68-0.91) had significantly affected the 3-year graft survival. CONCLUSIONS: DAA has a significant beneficial effect on LT. In the DAA era, graft survival for HCV-associated HCC has been significantly improving.

Retrospective Review of Trauma ICU Patients With and Without Palliative Care Intervention.

BACKGROUND: Older trauma patients present with poor preinjury functional status and more comorbidities. Advances in care have increased the chance of survival from previously fatal injuries with many left debilitated with chronic critical illness and severe disability. Palliative care (PC) is ideally suited to address the goals of care and symptom management in this critically ill population. A retrospective chart review was done to identify the impact of PC consults on hospital length of stay (LOS), ICU LOS, and surgical decisions. STUDY DESIGN: A Level 1 Trauma Center Registry was used to identify adult patients who were provided PC consultation in a selected 3-year time period. These PC patients were matched with non-PC trauma patients on the basis of age, sex, race, Glasgow Coma Scale, and Injury Severity Score. Chi-square tests and Student's t-tests were used to analyze categorical and continuous variables, respectively. Any p value >0.05 was considered statistically significant. RESULTS: PC patients were less likely to receive a percutaneous endoscopic gastric tube or tracheostomy. PC patients spent less time on ventilator support, spent less time in the ICU, and had a shorter hospital stay. PC consultation was requested 16.48 days into the patient's hospital stay. Approximately 82% of consults were to assist with goals of care. CONCLUSION: Specialist PC team involvement in the care of the trauma ICU patients may have a beneficial impact on hospital LOS, ICU LOS, and surgical care rendered. Earlier consultation during hospitalization may lead to higher rates of goal-directed care and improved patient satisfaction.