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1.
J Endourol ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35018788

RESUMO

PURPOSE: We evaluated our experience of a multidisciplinary approach to renal mass biopsy (RMB) for small renal masses (SRM) employing in-office ultrasound (US) guided biopsy by urology (24%), computed tomography (CT) or US biopsy by interventional radiology (IR) (79%), and endoscopic ultrasound-guided biopsy by gastroenterology (GI) (4%). METHODS: A single-institution retrospective review of patients who underwent RMB for SRM from May 2013 to August 2019 was conducted. Data regarding patient demographics, tumor characteristics, biopsy technique, histopathology, and management were collected. Diagnostic rates, concordance with final pathology, complications, and outcomes were analyzed. RESULTS: Of the 192 biopsies reviewed, 63% biopsies were malignant, 20% were benign, and 17% were non-diagnostic. Based on biopsy results, 71 patients (37%) elected active surveillance. Thirty-eight (20%) patients underwent cryoablation, 56 (29%) underwent partial nephrectomy (PN), 14 (7%) underwent radical nephrectomy (RN) and the remaining patients were treated elsewhere. The rate of surgery for benign pathology after pretreatment RMB was 3%. The concordance rate between biopsy and final pathology was 99% for malignancy, 96% for specific pathology subtype, and 85% for RCC grade. Median time from diagnosis to definitive treatment was 97 days (urology: 76, IR: 110 and GI: 54, p=0.002). Three (1.6%) Clavien I complications were reported. CONCLUSION: Our multidisciplinary approach to renal mass biopsy for clinical stage T1a demonstrated favorable safety and diagnostic rates, which effectively directed management strategies and minimized surgery for benign disease. Urologist performed office-biopsies significantly shortened the time from diagnosis to definitive treatment. Our experience with GI EUS biopsy has demonstrated feasibility and safety for tumors that were otherwise not accessible percutaneously.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34667130

RESUMO

BACKGROUND AND OBJECTIVES: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease primarily affecting the peripheral nervous system. However, several noncontrolled studies have suggested concomitant inflammatory CNS demyelination similar to multiple sclerosis. The aim of this study was to investigate an involvement of the visual pathway in patients with CIDP. METHODS: In this prospective cross-sectional study, we used high-resolution spectral-domain optical coherence tomography to compare the thickness of the peripapillary retinal nerve fiber layer and the deeper macular retinal layers as well as the total macular volume (TMV) in 22 patients with CIDP and 22 age-matched and sex-matched healthy control (HC) individuals. Retinal layers were semiautomatically segmented by the provided software and were correlated with clinical measures and nerve conduction studies. RESULTS: In patients with CIDP compared with healthy age-matched and sex-matched controls, we found slight but significant volume reductions of the ganglion cell/inner plexiform layer complex (CIDP 1.86 vs HC 1.95 mm3, p = 0.015), the retinal pigment epithelium (CIDP 0.38 vs HC 0.40 mm3, p = 0.02), and the TMV (CIDP 8.48 vs HC 8.75 mm3, p = 0.018). The ganglion cell layer volume and motor nerve conduction velocity were positively associated (B = 0.002, p = 0.02). DISCUSSION: Our data reveal subtle retinal neurodegeneration in patients with CIDP, providing evidence for visual pathway involvement, detectable by OCT. The results need corroboration in independent, larger cohorts.

3.
Dev Comp Immunol ; 126: 104265, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34555416

RESUMO

This study describes the construction and immunological characterization of a novel Salmonella gallinarium ghost vaccine to protect against S. gallinarium (SG) and S. Enteritidis (SE) serotypes. The SG ghost was designed to express N-terminus FliC (D0-D1 domain) and FimA retrieved from the SE genome, and the receptor-binding domain (RBD) of CD40L from the chicken as a single fusion construct. The construct was built in pJHL184, a phage lysis gene E-mediated ghost plasmid and the expression was confirmed by western blot resulting in an 85-kDa band. Chicken immunization was conducted by intramuscular route with SG ghost FliC-FimA-CD40L, vector control, or PBS alone in a prime-boost schedule. Antibody responses, cell-mediated immune responses (CMI), and cytokine induction was assessed in chicken demonstrating significantly high levels of IgY, CMI, cytokine responses in ghost immunized group delivering partial protection against SG wild type challenge and near complete protection against SE challenge wild type challenge.

4.
J Immunol ; 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853076

RESUMO

The anaphylatoxin C5a is core effector of complement activation. C5a exerts potent proinflammatory and immunomodulatory actions through interacting with its C5a receptors, C5aR1 and C5aR2, modulating multiple signaling and functional activities of immune cells. Native C5a contains a large N-linked glycosylation site at Asn64, which accounts for up to 25% of its m.w. To date, the vast majority of published studies examining C5a are performed using Escherichia coli-generated recombinant C5a, which is readily available from numerous commercial suppliers, but lacks this glycosylation moiety. However, a plasma-purified "native" form of C5a is also commercially available. The different size and glycosylation of these two C5a versions could have functional implications. Therefore, the current study aimed to compare recombinant human C5a to purified plasma-derived human C5a in driving the signaling and functional activities of human primary macrophages. We found that both versions of C5a displayed similar potencies at triggering C5aR1- and C5aR2-mediated cell signaling, but elicited distinct functional responses in primary human monocyte-derived macrophages. Multiple commercial sources of recombinant C5a, but not the plasma-purified or a synthetic C5a version, induced human monocyte-derived macrophages to produce IL-6 and IL-10 in a C5a receptor-independent manner, which was driven through Syk and NF-κB signaling and apparently not due to endotoxin contamination. Our results, therefore, offer caution against the sole use of recombinant human C5a, particularly in functional/cytokine assays conducted in human primary immune cells, and suggest studies using recombinant human C5a should be paired with C5aR1 inhibitors or purified/synthetic human C5a to confirm relevant findings.

5.
Eur Heart J Case Rep ; 5(11): ytab408, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34870085

RESUMO

Background: Pyopneumopericarditis is a very rare diagnosis that requires prompt recognition and urgent treatment. It denotes the presence of pus and air in the pericardium with associated inflammation of the fibrous pericardial sac. Case summary: A 49-year-old gentleman was admitted with pyopneumoperciarditis on a background of a previous uncomplicated Roux-en-Y gastric bypass surgery performed 7 years prior. He underwent emergency surgery for an omental patch repair of an ulcer perforation involving the diaphragm and pericardium. His inpatient stay was complicated by persistent seropurulent output from the pericardial drain, loculated pleural effusion, and deconditioning. Discussion: Management is extrapolated from the literature regarding purulent pericarditis. This condition albeit rare, requires swift recognition as without treatment mortality approaches 100%. Colchicine is an important adjunctive therapy postoperatively to prevent constrictive physiology.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34886581

RESUMO

India is witnessing an increase in the prevalence of multimorbidity. Oral health is related to overall health but is seldom included in the assessment of multimorbidity. Hence, this study aimed to estimate the prevalence of oral morbidity and explore its association with physical multimorbidity using data from Longitudinal Ageing Study in India (LASI). LASI is a nationwide survey amongst adults aged ≥ 45 years conducted in 2018. Descriptive analysis was performed on included participants (n = 59,764) to determine the prevalence of oral morbidity. Multivariable logistic regression assessed the association between oral morbidity and physical multimorbidity. Self-rated health was compared between multimorbid participants with and without oral morbidity. Oral morbidity was prevalent in 48.56% of participants and physical multimorbidity in 50.36%. Those with multimorbidity were at a higher risk of having any oral morbidity (AOR: 1.60 (1.48-1.73)) than those without multimorbidity. Participants who had only oral morbidity rated their health to be good more often than those who had physical multimorbidity and oral morbidity (40.84% vs. 32.98%). Oral morbidity is significantly associated with physical multimorbidity. Multimorbid participants perceived their health to be inferior to those with only oral morbidity. The findings suggest multidisciplinary health teams in primary care should include the management of oral morbidity and physical multimorbidity.

7.
Ear Hear ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34860720

RESUMO

OBJECTIVES: This study identified an association between cholesteatoma and progressive sensorineural hearing loss using a large pediatric longitudinal audiologic dataset. Cholesteatoma is a potential sequela of chronic otitis media with effusion, a commonly observed auditory pathology that can contribute to hearing loss in children. The purpose of this report is to (i) describe the process of identifying the association between cholesteatoma and progressive sensorineural hearing loss in a large pediatric dataset and (ii) describe the audiologic data acquired over time in patients identified with cholesteatoma-associated progressive sensorineural hearing loss. DESIGN: Records of patients included in the Audiologic and Genetics Database (n = 175,215 patients) were examined using specified criteria defining progressive hearing loss. A linear regression model examined the log frequency of all diagnostic codes in the electronic health record assigned to patients for a progressive hearing loss cohort compared with a stable hearing loss group. Based on findings from the linear regression analysis, longitudinal audiometric air (AC) and bone conduction (BC) thresholds were extracted for groups of subjects with cholesteatoma-associated progressive (n = 58 subjects) and stable (n = 55 subjects) hearing loss to further analyze changes in hearing over time. RESULTS: The linear regression analyses identified that diagnostic codes for cholesteatoma were associated with progressive sensorineural hearing loss in children. The longitudinal audiometric data demonstrated within-subject changes in masked BC sensitivity consistent with progressive sensorineural hearing loss in children diagnosed with cholesteatoma. Additional analyses showed that mastoidectomy surgeries did not appear to contribute to the observed progressive hearing loss and that a high number of cholesteatoma patients with progressive hearing loss had normal-hearing thresholds at their first test. CONCLUSIONS: The statistical analyses demonstrated an association between cholesteatoma and pediatric progressive sensorineural hearing loss. These findings inform clinical management by suggesting that children with cholesteatoma diagnoses may be at increased risk for progressive sensorineural hearing loss and should receive continued monitoring even after a normal masked BC baseline has been established.

8.
J Otolaryngol Head Neck Surg ; 50(1): 71, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34949220

RESUMO

BACKGROUND: Report the incidence of contralateral nodal failure rates in well-lateralized oropharyngeal carcinoma treated with upfront surgery and unilateral neck management. METHODS: Lateralized oropharyngeal carcinomas treated with upfront surgery using transoral robotic surgery (TORS) and unilateral neck management (unilateral neck dissection ± unilateral radiation treatment) were identified. Primary endpoint was contralateral regional control (CRC). Secondary endpoints were local control (LC), and overall survival (OS). RESULTS: Thirty-two patients were included. Pathologic T categories included 66% pT1, 31% pT2 and 3% pT3. Nodal diseases comprised 41% N0 and 47% N1 (AJCC 8th). Twenty-three (72%) patients had HPV related tumors. 3-years CRC, LC and OS were 100%, 96% (89-100) and 96% (CI 89-100). One patient developed a second primary with contralateral nodal disease. Only one patient died from another primary cancer. CONCLUSION: In selected patients with lateralized oropharyngeal cancer, treatment with TORS and ipsilateral management of the neck may be oncologically safe without significant risk of contralateral failure. LEVEL OF EVIDENCE: Level 2.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Orofaríngeas , Procedimentos Cirúrgicos Robóticos , Carcinoma de Células Escamosas/cirurgia , Humanos , Esvaziamento Cervical , Neoplasias Orofaríngeas/cirurgia , Estudos Retrospectivos
9.
World Neurosurg ; 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34971836

RESUMO

BACKGROUND: The use of 5-ALA for intraoperative protoporphyrin IX (PpIX) fluorescent imaging in the resection of malignant gliomas has been demonstrated to improve tumor visualization, increase extent of resection, and extend progression-free survival. The current technique for visualization of 5-ALA consists of excitation and emission filters built into the operating microscope. However, there are notable limitations to this process, including low quantum yield, expense, and masking of surrounding anatomy. METHODS: We present three cases in which three separate methods were employed for visualizing fluorescence. The devices reported are 1) a low-cost blue light flashlight and 2) a low-cost headlamp, and 3) the first reported case of the new Design for Vision® REVEAL™ FGS (Fluorescence Guided Surgery) 5-ALA fluorescent headlight and loupes. The aim of the study is to provide confirmation that tumor fluorescence can be observed using commercially-available products other than the microscope. RESULTS: We demonstrate through three intraoperative cases that a variety of devices can produce visible fluorescence of the high-grade tumor and allow for simultaneous real-time visualization of the adjacent brain parenchyma and vasculature. The REVEAL™ FGS system appears to offer increased fluorescence emission compared to all other methods, including the microscope. CONCLUSIONS: Our study demonstrates the feasibility of using blue/ultraviolet light supplied by a commercially available, inexpensive flashlight or headlamp to visualize 5-ALA fluorescence in high-grade gliomas. We also provide the first documentation of intraoperative use of the new Design for Vision® REVEAL™ FGS 5-ALA fluorescent headlight and loupes and report on the experience. Lack of an operative microscope capable of fluorescent illumination should not be a limiting factor in performing fluorescent-guided glioma resection.

10.
ACS Pharmacol Transl Sci ; 4(6): 1808-1817, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34927012

RESUMO

The complement activation peptide C5a is a key mediator of inflammation that is associated with numerous immune disorders. C5a binds and activates two seven-transmembrane receptors, C5aR1 and C5aR2. Experimentally, C5a is utilized to investigate C5a receptor biology and to screen for potential C5aR1/C5aR2 therapeutics. Currently, laboratory sources of C5a stem from either isolation of endogenous C5a from human serum or most predominantly via recombinant expression. An alternative approach to C5a production is chemical synthesis, which has several advantages, including the ability to introduce non-natural amino acids and site-specific modifications whilst also maintaining a lower probability of C5a being contaminated with microbial molecules or other endogenous proteins. Here, we describe the efficient synthesis of both human (hC5a) and mouse C5a (mC5a) without the need for ligation chemistry. We validate the synthetic peptides by comparing pERK1/2 signaling in CHO-hC5aR1 cells and primary human macrophages (for hC5a) and in RAW264.7 cells (for mC5a). C5aR2 activation was confirmed by measuring ß-arrestin recruitment in C5aR2-transfected HEK293 cells. We also demonstrate the functionalization of synthetic C5a through the introduction of a lanthanide chelating cage to facilitate a screen for the binding of ligands to C5aR1. Finally, we verify that the synthetic ligands are functionally similar to recombinant or native C5a by assessing hC5a-induced neutrophil chemotaxis in vitro and mC5a-mediated neutrophil mobilization in vivo. We propose that the synthetic hC5a and mC5a described herein are valuable alternatives to recombinant or purified C5a for in vitro and in vivo applications and add to the growing complement reagent toolbox.

11.
bioRxiv ; 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34845444

RESUMO

Metagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present contamination-free metagenomic DNA sequencing (Coffee-seq), a metagenomic sequencing assay that is robust against environmental contamination. The core idea of Coffee-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied Coffee-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of inflammatory bowel disease in blood.

12.
Nature ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819669

RESUMO

The cell is a multi-scale structure with modular organization across at least four orders of magnitude1. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately2,3. Here we integrate immunofluorescence images in the Human Protein Atlas4 with affinity purifications in BioPlex5 to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.

13.
Oncotarget ; 12(22): 2252-2265, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34733416

RESUMO

Breast cancer patients diagnosed with HR+/HER2- tumors face a persistent risk of distant recurrence long after completion of their treatment. Strategies to induce anti-tumor immune responses could complement standard-of-care therapies for these patients. The current study was performed to examine the feasibility, safety and immunogenicity of adding P10s-PADRE to standard-of-care chemotherapy in HR+/HER2- early-stage breast cancer patients. Twenty-five subjects were treated in a single-arm Phase Ib clinical trial. Five different immunization schedules were considered to evaluate the feasibility of eliciting an immune response. The primary immunogenicity endpoint was antibody titer. The expression of several activation markers on natural killer (NK) cells and serum concentrations of Th1/Th2 cytokines were also examined. The percentage of tumor-infiltrating lymphocytes (TILs) was determined. Antibody response was superior in schedule C where 3 weekly immunizations preceded the first dose of chemotherapy. A significant change in CD16, NKp46 and CD94 expression levels on NK cells and a rise in serum content of IFN-γ was observed after treatment. Schedule C showed an increase in TILs in residual lesions. The combination therapy is safe and immunogenic with treatment schedule C being immunologically promising. Randomized trials focused on long-term survival outcomes are needed to evaluate clinical benefits.

14.
J Med Chem ; 64(22): 16598-16608, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34762432

RESUMO

The anaphylatoxin C5a is a complement peptide associated with immune-related disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2. Multiple C5a peptide agonists have been developed to interrogate the C5a receptor function but none show selectivity for C5aR1. To address these limitations, we developed potent and stable peptide C5aR1 agonists that display no C5aR2 activity and over 1000-fold selectivity for C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated calcium mobilization and pERK1/2 signaling but not ß-arrestin recruitment, and BM221, which exhibits no signaling bias. Both ligands are functionally similar to C5a in human macrophage cytokine release assays and in a murine in vivo neutrophil mobilization assay. BM213 showed antitumor activity in a mouse model of mammary carcinoma. We anticipate that these C5aR1-selective agonists will be useful research tools to investigate C5aR1 function.

15.
Int J Gynecol Cancer ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799418

RESUMO

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

16.
Clin Neurol Neurosurg ; 211: 107016, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34823154

RESUMO

BACKGROUND: Brain metastases are the most common central nervous system (CNS) tumors, occurring in 300,000 people per year in the US. While there are immediate local benefits to surgical resection for dominant lesions, including reduction of tumor burden and edema, the survival benefits of surgical resection, over radiosurgery, remains unclear. METHODS: The University of Pennsylvania Health System database was retrospectively reviewed for patients presenting with multiple brain metastases from 1/1/16-8/31/18 with one dominant lesion > 2 cm in diameter, who underwent initial treatment with either resection of the dominant lesion or Gamma Knife radiosurgery (GKS). Inclusion criteria were age > 18, > 1 brain metastasis, and presence of a dominant lesion (>2 cm). We analyzed factors associated with mortality. RESULTS: 129 patients were identified (surgery=84, GKS=45). The median number of intracranial metastases was 3 (IQR: 2-5). The median diameter of the largest lesion was 31 mm (IQR: 25-38) in the surgery group vs 21 mm (IQR: 20-24) in the GKS group (p < 0.001). Mortality did not differ between surgery and GKS patients (69.1% vs 77.8%, p = 0.292). In a multivariate survival analysis, there was no difference in mortality between the surgery and GKS cohorts (aHR: 1.35, 95% CI: 0.74-2.45 p = 0.32). Pre-operative KPS (aHR: 0.97, 95% CI: 0.95-0.99, p = 0.004), CNS radiotherapy (aHR: 0.33, 95% CI: 0.19-0.56 p < 0.001), chemotherapy (aHR: 0.27, 95% CI: 0.15-0.47, p < 0.001), and immunotherapy (aHR: 0.41, 95% CI: 0.25-0.68, p = 0.001) were associated with decreased mortality. CONCLUSION: In our institution, patients with multiple brain metastases and one symptomatic dominant lesion demonstrated similar survival after GKS when compared with up-front surgical resection of the dominant lesion.

17.
Int J Surg ; 96: 106167, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34752951

RESUMO

INTRODUCTION: Colorectal anastomotic leaks (AL) are associated with high morbidity and mortality. Management of AL and its intra-operative decision making is often difficult. The aim of this multi-centre study is to explore different management strategies, including different surgical options, and analyse rates and patterns of failure of initial management. METHODS: All consecutive patients who had a confirmed AL after elective colorectal resections from 1st January 2014 to 31st December 2019 were included at seven hospitals across the East of England Region. Morbidity (length of stay, and failures) and mortality were compared across the different management strategies, and survival analyses were performed (Clinicaltrials.gov ID: NCT05000580). RESULTS: Across all seven hospitals, a total of 3391 elective resection were done during the study period. 201 (5.9%) consecutive patients with confirmed AL were included. The initial treatment was conservative in 102(50.7%). 19 patients (9.5%) had a radiological procedure, 80 (39.8%) of patients required surgery as an initial treatment post AL. Of those who initially did not have a surgical intervention (n = 121), 10% (n = 12/121) eventually required laparotomy, 2 additional patients required transanal drainage. Ultimately 45.8% (n = 92/201) of the whole population eventually required a laparotomy. Patients managed conservatively had a shorter LOS when compared to either radiological drainage or surgical patients. Patients with a defunctioning stoma are more likely to have a successful conservative management and shorter LOS. 90-day mortality across the entire population was 8.1%. There were no significant differences in mortality or long-terms survival between the different initial treatment modalities or whether the leak was right or left sided. CONCLUSION: Despite initial conservative, antibiotic and radiological intervention being successful in the majority of patients, two out of five patients will still require a laparotomy and over a quarter of patients will have an end stoma.

18.
Elife ; 102021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34734805

RESUMO

Acoustic overexposure and aging can damage auditory synapses in the inner ear by a process known as synaptopathy. These insults may also damage hair bundles and the sensory transduction apparatus in auditory hair cells. However, a connection between sensory transduction and synaptopathy has not been established. To evaluate potential contributions of sensory transduction to synapse formation and development, we assessed inner hair cell synapses in several genetic models of dysfunctional sensory transduction, including mice lacking transmembrane channel-like (Tmc) 1, Tmc2, or both, in Beethoven mice which carry a dominant Tmc1 mutation and in Spinner mice which carry a recessive mutation in transmembrane inner ear (Tmie). Our analyses reveal loss of synapses in the absence of sensory transduction and preservation of synapses in Tmc1-null mice following restoration of sensory transduction via Tmc1 gene therapy. These results provide insight into the requirement of sensory transduction for hair cell synapse development and maturation.

19.
Biomaterials ; 279: 121226, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34736150

RESUMO

This study describes an efficient eukaryotic expression system (pJHL204) built into the Salmonella delivery system to enhance the essential efficacy and effectiveness of conventional DNA therapy. The expression system utilizes RNA-dependent RNA polymerase activity (RdRp) of Semiliki Forest Virus attributing to dramatic antigen expression by cytoplasmic mRNA amplification. Functional characterization of the pJHL204 by in vitro and in vivo transfection studies revealed the improved expression of mRNA at least 150 folds than the RdRp mutant plasmid under in vitro conditions. Using green fluorescence protein (GFP) and mCherry as bait proteins this system was extensively characterized for plasmid delivery capacity, antigen expression, and safety using in vivo and in vitro models by employing flow cytometry, fluorescence microscopy, and immunohistochemical staining. Employment of Salmonella as a carrier significantly extends plasmid in vivo survivability and prolongs the effective duration until the elimination of the Salmonella carrier strain in the host. The strategy can be easily adapted for P2A connected multiple antigen delivery in a single vector system due to the significantly high cargo capacity of Salmonella. A mouse challenge study was carried out utilizing P2A connected H1N1 hemagglutinin (HA) and neuraminidase (NA) via the Salmonella carrier strain JOL2500 significantly reduced viral activity and protected mice against the H1N1 challenge and demonstrates potential to redefine in vivo DNA therapy as a reliable and safe system to treat human diseases using useful microbes like Salmonella.

20.
Transpl Immunol ; 69: 101480, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34619318

RESUMO

BACKGROUND: Chronic lung transplant rejection occurs in over 50% of lung transplant recipients and mechanism of chronic rejection is unknown. Evaluation of potential mechanism of exosomes from lung transplant recipients diagnosed with respiratory viral infection (RVI) in inducing chronic lung allograft dysfunction (CLAD). METHOD: Exosomes were isolated from lung transplant recipients followed by DNA and RNA isolation from exosomes. Cell signaling mechanisms were studied by co-culturing exosomes with human epithelial cells. Mice were immunized with exosomes and lung homogenates were studied for immune signaling proteins. RESULTS: Exosomes from lung transplant recipients with RVI carry nucleic acids which are capable of inducing innate immune signaling, endoplasmic reticulum stress, and epithelial mesenchymal transition. CONCLUSION: Therefore, we propose that RVI can lead to induction of exosomes that initiate the process leading to CLAD in mice models. These novel findings identified the molecular mechanisms by which RVI increases the risk of CLAD.

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