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PURPOSE: 5-FU/cisplatin and twice-daily radiation (FCT) or gemcitabine and once daily radiation (GD) are effective chemoradiation (CRT) regimens for bladder sparing treatment of muscle-invasive bladder cancer (MIBC). This trial evaluated these regimens and demonstrated efficacy with either regimen at 3 years. With further follow-up, longer term results are reported here. METHODS AND MATERIALS: Patients with cT2-4a MIBC were randomized to FCT or GD. Patients had a transurethral resection and induction CRT to 40 Gy. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others had cystectomy. Adjuvant gemcitabine/cisplatin chemotherapy was administered. The primary endpoint was freedom from distant metastasis (FDM). This updated analysis reports 7-year data. Toxicity and efficacy endpoints, including bladder intact distant metastasis free survival (BI-DMFS) were also assessed. RESULTS: From 12/2008 to 4/2014, 70 patients were enrolled; 66 eligible for analysis, 33 per arm. Median follow-up was 9.1 years for eligible living patients. At 7 years, FDM was 65% and 73% for FCT and GD, respectively. BI-DMFS was 58% (95% CI: 41 - 76) and 68% (95% CI: 51-84), respectively. The post-hoc hazard ratio of 0.75 (95% CI: 0.37-1.55) showed no difference between treatments (p=0.44). Overall survival at 7 years was 48% and 59%. There were 4 and 5 cystectomies performed for FCT and GD, respectively. In the FCT arm, there were 5 (16%), 1 (3%) and 0 grade 3, 4 and 5 late toxicities reported. In the GD arm, there were 7 (23%), 0 and 0. CONCLUSIONS: Both regimens maintained high FDM rates at 7 years. Cystectomy rates were low and overall survival rates high on both arms. Late toxicity rates were low. Either gemcitabine and daily radiation or a cisplatin-based regimen are effective bladder sparing therapies.
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Enterovirus A71 (EV-A71) causes Hand, Foot, and Mouth Disease and has been clinically associated with neurological complications. However, there is a lack of relevant models to elucidate the neuropathology of EV-A71 and its mechanism, as the current models mainly utilize animal models or immortalized cell lines. In this study, we established a human motor neuron model for EV-A71 infection. Single cell transcriptomics of a mixed neuronal population reveal higher viral RNA load in motor neurons, suggesting higher infectivity and replication of EV-A71 in motor neurons. The elevated RNA load in motor neurons correlates with the downregulation of ferritin-encoding genes. Subsequent analysis confirms that neurons infected with EV-A71 undergo ferroptosis, as evidenced by increased levels of labile Fe2+ and peroxidated lipids. Notably, the Fe2+ chelator Deferoxamine improves mitochondrial function and promotes survival of motor neurons by 40% after EV-A71 infection. These findings deepen understanding of the molecular pathogenesis of EV-A71 infection, providing insights which suggest that improving mitochondrial respiration and inhibition of ferroptosis can mitigate the impact of EV-A71 infection in the central nervous system.
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Enterovirus Humano A , Infecções por Enterovirus , Ferroptose , Neurônios Motores , Ferroptose/efeitos dos fármacos , Humanos , Enterovirus Humano A/fisiologia , Enterovirus Humano A/genética , Enterovirus Humano A/efeitos dos fármacos , Neurônios Motores/virologia , Neurônios Motores/metabolismo , Infecções por Enterovirus/virologia , Infecções por Enterovirus/metabolismo , Replicação Viral , Mitocôndrias/metabolismo , Desferroxamina/farmacologia , Carga Viral , Ferro/metabolismo , Ferritinas/metabolismo , Ferritinas/genéticaRESUMO
The transplantation of spinal cord progenitor cells (SCPCs) derived from human-induced pluripotent stem cells (iPSCs) has beneficial effects in treating spinal cord injury (SCI). However, the presence of residual undifferentiated iPSCs among their differentiated progeny poses a high risk as these cells can develop teratomas or other types of tumors post-transplantation. Despite the need to remove these residual undifferentiated iPSCs, no specific surface markers can identify them for subsequent removal. By profiling the size of SCPCs after a 10-day differentiation process, we found that the large-sized group contains significantly more cells expressing pluripotent markers. In this study, we used a sized-based, label-free separation using an inertial microfluidic-based device to remove tumor-risk cells. The device can reduce the number of undifferentiated cells from an SCPC population with high throughput (ie, >3 million cells/minute) without affecting cell viability and functions. The sorted cells were verified with immunofluorescence staining, flow cytometry analysis, and colony culture assay. We demonstrated the capabilities of our technology to reduce the percentage of OCT4-positive cells. Our technology has great potential for the "downstream processing" of cell manufacturing workflow, ensuring better quality and safety of transplanted cells.
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Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Traumatismos da Medula Espinal , Humanos , Medula Espinal/patologia , Diferenciação Celular/fisiologia , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/patologiaRESUMO
BACKGROUND: Genitourinary malignancies have a substantial impact on men and women in the USA as they include three of the ten most common cancers (prostate, renal, and bladder). Other urinary tract cancers are less common (testis and penile) but still have profound treatment implications related to potential deficits in sexual, urinary, and reproductive function. Evidenced-based practice remains the cornerstone of treatment for urologic malignancies. METHODS: The authors reviewed the literature in consideration of the four top articles influencing clinical practice in the prior calendar year, 2022. RESULTS: The PROTECT trial demonstrates favorable 15-years outcomes for active monitoring of localized prostate cancer. The SEMS trial establishes retroperitoneal lymph node dissection as a viable option for patients with seminoma of the testis with limited retroperitoneal lymph node metastases. CheckMate 274 supports adjuvant immunotherapy following radical cystectomy for muscle-invasive bladder cancer with a high risk of recurrence. Data reported from the IROCK consortium reinforce stereotactic ablative radiotherapy as an option for localized renal cell carcinoma. CONCLUSION: The care for patients with urologic cancers has been greatly improved through advances in surgical, medical, and radiation oncologic treatments realized through prospective randomized clinical trials and large multicenter collaborative groups.
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Neoplasias Renais , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Urologia , Feminino , Humanos , Masculino , Cistectomia , Neoplasias Renais/cirurgia , Excisão de Linfonodo , Estudos Prospectivos , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/cirurgiaRESUMO
INTRODUCTION: Though urology attracts well-qualified applicants, students are not typically provided exposure to this smaller specialty until later in their medical education. While simulation-based training continues to supplement medical education, there is a lack of programming to teach specialty-specific procedural skills to medical students and those outside the specialty. We report a half-day simulation and didactic-based approach to increase exposure to urology to interested second-year medical students. METHODS: A half-day didactic- and simulation-based session was offered to second-year medical students (N=57). After a didactic-based overview of the specialty performed by urology providers and a surgical educator, the students participated in small-group simulations, including hands-on simulations. The students completed a post-curriculum survey measuring knowledge gains and soliciting feedback on the session. RESULTS: Students were 57.1% Caucasian, 66.7% female, with a mean age of 24.2 years; 80% stated they were potentially interested in pursuing a surgical specialty such as urology prior to the start of the session. Students reported pre- to post-curriculum gains in knowledge (mean=37%) about a career in urology and basic urologic procedures (p<0.001). Participants were also likely to recommend the curriculum to their peers (p<0.001). CONCLUSIONS: Given that exposure to urology in medical school is usually limited and offered later in training, a half-day didactic- and simulation-based experience for second-year students provides an early introduction and experience within the specialty and its common bedside procedures.
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PURPOSE: The primary objective of this study was to evaluate how the utilization of virtual surgical planning (VSP) and the epidemiological profile of patients undergoing orthognathic surgery (OGS) have changed in the past decade. METHODS: The records of patients who had undergone orthognathic surgery at a national dental hospital were reviewed. Trends in VSP, epidemiological data, presentation of dentofacial deformity, and management details were recorded. RESULTS: A total of 1184 patients were included in this study. The majority of the patients seeking treatment in this dental hospital were young Chinese adults with dentofacial deformities requiring bimaxillary surgeries. Most patients presented with a skeletal Class III pattern (79.0%), and asymmetry was diagnosed in 80.8% of all cases. CONCLUSION: There was an initial slow pick-up rate for VSP, but this rapidly increased to a high adoption rate of 98.7-100% between 2019 and 2021. Together with an increasing body of evidence suggesting greater accuracy in VSP, utilization in this technology can be enhanced with greater familiarity with the technology and improvements in the VSP services.
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Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
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COVID-19 , Humanos , Animais , COVID-19/patologia , Mastócitos/patologia , SARS-CoV-2 , Pulmão/patologia , Inflamação/patologiaRESUMO
The use of advanced preclinical models has become increasingly important in drug development. This is particularly relevant in bladder cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (chemotherapy, radiotherapy, immunotherapy, and/or surgery) are largely absent. Patient-derived and clinically relevant models including patient-derived xenografts (PDX), organoids, and conditional reprogramming (CR) of cell cultures efficiently generate numerous models and are being used in both basic and translational cancer biology. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have utilized CR technology to conduct bladder cancer research.
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Neoplasias da Bexiga Urinária , Animais , Humanos , Modelos Animais de Doenças , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/patologia , Técnicas de Cultura de Células , Desenvolvimento de MedicamentosRESUMO
INTRODUCTION: Simulation-based medical education continues to gain popularity as the clinical environment requires exemplary patient safety while simultaneously maximizing the learner's educational experience. There is a current lack of urology-focused medical student education curricula in the literature. Here, we present the findings of a didactic and simulation-based medical student advanced "urology boot camp" curriculum, which was designed for learners interested in pursuing careers in urology. METHODS: Twenty-nine fourth-year urology-dedicated medical students completing their subinternship at our institution during the 2018-2019 academic year participated in an advanced hands-on simulation "boot camp," which taught both simple and advanced Foley catheter placement, manual and continuous bladder irrigation, and diagnostic cystoscopy. Knowledge acquisition was assessed through quizzes administered before and after completing electronic modules, and a post-simulation survey assessing learners' confidence in their knowledge and skill set, as well as their satisfaction with the curriculum. RESULTS: Medical students demonstrated significant gains in knowledge from pre-test (mean 73.7%) to post-test (mean 94.5%, P < .001), which was consistent across each simulation procedure. Participants self-reported significant improvement in confidence with the procedures from before to after the educational intervention (P < .001). Students also found the curriculum to be beneficial to their understanding of the subject matter (P < .001), would recommend this curriculum to other medical students (P < .001), and thought it better prepared them to meet expected ACGME (Accreditation Council for Graduate Medical Education) milestones (P < .001). CONCLUSIONS: Findings from our advanced "boot camp" simulation curriculum demonstrated successful gains in knowledge and confidence following learning modules and hands-on simulation, indicating that this type of educational intervention could be beneficial in improving exposure to skills and developing confidence prior to urology internship and junior residency.
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Estudantes de Medicina , Urologia , Humanos , Urologia/educação , Competência Clínica , Currículo , Educação de Pós-Graduação em Medicina/métodosRESUMO
The 3rd-7th edition of the American Joint Committee on Cancer had 3 categories for positive lymph nodes (pN1-3) in upper urinary tract carcinomas. The 8th edition removed pN3, defining pN1 as one lymph node with a tumor deposit ≤2 cm and pN2 as a node with a tumor deposit >2 cm or metastases in multiple nodes. The aim of this study was to assess if the current pN categories impact survival in renal pelvic and ureteral carcinomas. Nephroureterectomies performed at our institution for primary upper urinary tract carcinomas between 2010 and 2019 were reviewed. Lymphadenectomy was performed in 73.3% of cases (151/206, median = 9 nodes). Eighty-one (53.6%) patients were deceased at the last review (pN0, 53 [44.5%]; pN1-2, 28 [87.5%]). There was no difference in overall or recurrence-free survival between pN1 and pN2 with 5-year overall survival (95% confidence interval) of pN0, 60.7% (52.0-70.8%); pN1, 15.4% (4.3-35.2%); and pN2, 21.1% (8.8-40.3%). The metastatic deposit size threshold of 2 cm, the number of positive lymph nodes, as well as extranodal extension did not correlate with overall or recurrence-free survival. As such, pN1 and pN2 were grouped together with a 5-year overall survival of 18.8% (9.12-28.6%). The current stratification of upper urinary tract carcinomas into pN1 and pN2 does not provide prognostic information, and both yield a stage IV classification, regardless of pT or pM category. Therefore, we recommend further simplification of pN classification into one category for regional lymph node metastasis, irrespective of the lymph node deposit size or number of positive lymph nodes.
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Carcinoma , Sistema Urinário , Neoplasias Urológicas , Humanos , Extensão Extranodal/patologia , Metástase Linfática/patologia , Prognóstico , Carcinoma/patologia , Neoplasias Urológicas/patologia , Linfonodos/cirurgia , Linfonodos/patologia , Sistema Urinário/patologia , Estadiamento de Neoplasias , Excisão de Linfonodo , Estudos RetrospectivosRESUMO
The neuroinflammatory response that is elicited after spinal cord injury contributes to both tissue damage and reparative processes. The complex and dynamic cellular and molecular changes within the spinal cord microenvironment result in a functional imbalance of immune cells and their modulatory factors. To facilitate wound healing and repair, it is necessary to manipulate the immunological pathways during neuroinflammation to achieve successful therapeutic interventions. In this review, recent advancements and fresh perspectives on the consequences of neuroinflammation after SCI and modulation of the inflammatory responses through the use of molecular-, cellular-, and biomaterial-based therapies to promote tissue regeneration and functional recovery will be discussed.
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BACKGROUND: Very preterm infants are at risk for neurodevelopmental impairment because of postnatal morbidities. This study aims to (1) compare the outcomes of very-low-birth-weight (VLBW) infants in Singapore during two time periods over a decade; 2) compare performances among Singaporean neonatal intensive care units (NICUs); and 3) compare a Singapore national cohort with one from the Australian and New Zealand Neonatal Network (ANZNN). METHODS: Singapore national data on VLBW infants born during two periods, 2007-2008 (SG2007, n = 286) and 2015-2017 (SG2017, n = 905) were extracted from patient medical records. The care practices and clinical outcomes among three Singapore NICUs were compared using SG2017 data. Third, using data from the ANZNN2017 annual report, infants with gestational age (GA) ≤29 weeks in SG2017 were compared with their Oceania counterparts. RESULTS: SG2017 had 9.9% higher usage of antenatal steroids (p < 0.001), 8% better survival for infants ≤26 weeks (p = 0.174), and used 12.7% lesser nonsteroidal anti-inflammatory drugs for patent ductus arteriosus closure (p < 0.001) than those of SG2007 cohort. Rate of late-onset sepsis (LOS) was almost halved (7.4% vs. 14.0%, p < 0.001), and exclusive human milk feeding after discharge increased threefold (p < 0.001). SG2017, in contrast, had a higher rate of chronic lung disease (CLD) (20.0% vs. 15.1%, p = 0.098). Within SG2017, the rates of LOS, CLD, and human milk feeding varied significantly between the three NICUs. When compared with ANZNN2017, SG2017 had significantly lower rates of LOS for infants ≤25 weeks (p = 0.001), less necrotizing enterocolitis for infants ≤27 weeks (p = 0.002), and less CLD across all GA groups. CONCLUSION: Postnatal morbidities and survival rates for VLBW infants in Singapore have improved over a decade. Outcomes for VLBW infants varied among three Singapore NICUs, which provide a rationale for collaboration to improve clinical quality. The outcomes of Singaporean VLBW infants were comparable to those of their ANZNN counterparts.
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Recém-Nascido Prematuro , Sepse , Recém-Nascido , Lactente , Humanos , Feminino , Gravidez , Estudos de Coortes , Singapura/epidemiologia , Austrália , Recém-Nascido de muito Baixo Peso , Mortalidade Infantil , MorbidadeRESUMO
According to the American Joint Cancer Committee, pT3 renal pelvic carcinoma is defined as tumor invading the renal parenchyma and/or peripelvic fat and is the largest pT category, with notable survival heterogeneity. Anatomical landmarks within the renal pelvis can be difficult to discern. Using glomeruli as a boundary to differentiate renal medulla invasion from renal cortex invasion, this study aimed to compare patient survival of pT3 renal pelvic urothelial carcinoma on the basis of the extent of renal parenchyma invasion and, thereafter, determine whether redefining pT2 and pT3 improves pT correlation with survival. Cases with primary renal pelvic urothelial carcinoma were identified through a review of pathology reports from nephroureterectomies completed at our institution from 2010 to 2019 (n = 145). Tumors were stratified by pT, pN, lymphovascular invasion, and invasion of the renal medulla versus invasion of the renal cortex and/or peripelvic fat. Overall survival between groups was compared using Kaplan-Meier survival models and Cox regression multivariate analysis. pT2 and pT3 tumors had similar 5-year overall survival, with multivariate analysis demonstrating an overlap between hazard ratios (HRs) for pT2 (HR, 2.20; 95% CI, 0.70-6.95) and pT3 (HR, 3.15; 95% CI, 1.63-6.09). pT3 tumors with peripelvic fat and/or renal cortex invasion had a 3.25-fold worse prognosis than pT3 tumors with renal medulla invasion alone. Furthermore, pT2 and pT3 tumors with only renal medulla invasion had similar overall survival, whereas pT3 tumors with peripelvic fat and/or renal cortex invasion had a worse prognosis (P = .00036). Reclassifying pT3 tumors with only renal medulla invasion as pT2 yielded greater separation between survival curves and HR. Thus, we recommend redefining pT2 renal pelvic carcinoma to include renal medulla invasion and restricting pT3 to peripelvic fat and/or renal cortex invasion to improve the prognostic accuracy of pT classification.
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Carcinoma de Células de Transição , Neoplasias Renais , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/patologia , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/patologia , Invasividade Neoplásica/patologia , Neoplasias Renais/patologia , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: "One-minute preceptor" (OMP) is a well-established educational technique; however, primary literature on OMP lacks a tool to assess behavioral change after delivery of curricula.Primary aim of this pilot study was to design a checklist for direct observation of teachers using OMP on general medicine rounds and obtain inter-rater reliability evidence for the checklist. METHODS: This study pilots an internally designed 6-item checklist to assess change in directly observed behavior. We describe the process of developing the checklist and training the observers. We calculated a percent agreement and Cohen's kappa to assess inter-rater reliability. RESULTS: Raters had a high percent agreement ranging from 0.8 to 0.9 for each step of OMP. Cohen's kappa ranged from 0.49 to 0.77 for the five OMP steps. The highest kappa obtained was for getting a commitment (κ = 0.77) step, whereas the lowest agreement was for correcting mistakes (κ = 0.49). CONCLUSION: We showed a percent agreement ≥0.8 and moderate agreement based on Cohen's kappa with most steps of OMP on our checklist. A reliable OMP checklist is an important step in further improving the assessment and feedback of resident teaching skills on general medicine wards.
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Lista de Checagem , Pacientes Internados , Humanos , Projetos Piloto , Reprodutibilidade dos Testes , CurrículoRESUMO
BACKGROUND: Acute necrotizing encephalopathy of childhood (ANEC) is a rare parainfectious neurological disorder. ANEC is associated with a high mortality rate and poor neurological outcomes. ANEC is postulated to arise from immune-mediated or metabolic processes driven by viral infections. Although there have been some case reports of acute necrotizing encephalopathy with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfection in adults, paediatric cases are rare. METHODS: A single case report of SARS-CoV-2-related ANEC in an 11-year-old boy is presented through retrospective chart review. Literature search was performed using PubMed, Embase, Cochrane database, and Google Scholar to compare and analyze similar cases of parainfectious immune-mediated encephalopathies related to SARS-CoV-2 in children. RESULTS: An 11-year-old boy with acute SARS-CoV-2 infection presented with ophthalmoplegia, ataxia, and aphasia. Neuroimaging findings demonstrated significant swelling and signal changes in bilateral thalami, brainstem, and cerebellar hemispheres, consistent with ANEC. His high ANEC Severity Score indicated poor neurological prognosis. Treatment with a combination of early steroid therapy, intravenous immunoglobulin therapy, and targeted interleukin 6 (IL-6) blockade yielded good neurological improvements. Literature search identified 19 parainfectious immune-mediated neurological disorders related to SARS-CoV-2 in children. The only other pediatric ANEC case identified was postinfectious and thus not included. CONCLUSIONS: This is the first report of a pediatric case of SARS-CoV-2-related ANEC, which responded well to early immunotherapy, including IL-6 blockade. Early immunotherapy with IL-6 blockade can be considered as an adjunct in managing severe ANEC.
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COVID-19 , Encefalite , Doenças do Sistema Nervoso , Criança , Humanos , Masculino , COVID-19/complicações , Tratamento Farmacológico da COVID-19 , Encefalite/complicações , Interleucina-6 , Doenças do Sistema Nervoso/etiologia , Estudos Retrospectivos , SARS-CoV-2RESUMO
Zika virus (ZIKV) became a public health concern when it re-emerged in 2015 owing to its ability to cause congenital deformities in the fetus and neurological complications in adults. Despite extensive data on protection, the interplay of protective and pathogenic adaptive immune responses toward ZIKV infection remains poorly understood. In this study, using a T-cellâdeficient mouse model that retains persistent ZIKV viral titers in the blood and organs, we show that the adoptive transfer of CD8+ T cells led to a significant reduction in viral load. This mouse model reveals that ZIKV can induce grossly visible auricular dermatitis and blepharitis, mediated by ZIKV-specific CD8+ T cells. Single-cell RNA sequencing of these causative CD8+ T cells from the ears shows an overactivated and elevated cytotoxic signature in mice with severe symptoms. Our results strongly suggest a role for CD8+ T-cellâassociated pathologies after ZIKV infection in CD4+ T-cellâimmunodeficient patients.
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Blefarite , Dermatite , Infecção por Zika virus , Zika virus , Camundongos , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Modelos Animais de DoençasRESUMO
VY closure of the Le Fort 1 incision may commonly be indicated to mitigate the lip shortening effects of maxillary advancement. The objective of this systematic review was to investigate if VY closure prevents lip shortening when compared with conventional continuous closure (CS) methods, in patients who underwent le fort 1 maxillary advancement. PubMed, Embase, and Cochrane Library databases were accessed. Hand searching was also performed. Observational studies, non-randomised and randomized controlled trials were included if Le Fort 1 maxillary advancement was performed to correct a dentofacial deformity. Comparisons were made between VY and CS, and morphological changes to the upper lip were evaluated. The demographic data, study methodology, magnitude of maxillary movements and outcomes related to the lip morphology (length, vermillion exposure, thickness and angulation) were extracted. The search yielded 487 articles. Six studies were included after the application of the selection criteria. A total of 100 and 94 patients received CS and VY respectively. VY was not found to reliably prevent lip shortening. VY was more likely to mitigate lip shortening when there is a large maxillary advancement. It was consistent for a protrusive or "rolled-out" lip morphology to occur after a VY closure. This was demonstrated by the increase in lip vermillion exposure, thickness, and angulation. VY closure was a useful adjunctive technique in patients undergoing large maxillary advancements to mitigate the lip shortening effect from the procedure. Surgeons who employ this technique must also be aware of the consequence of a more protrusive lip with increased vermillion exposure and assess if this would be aesthetically desirable for the individual patient.
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Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.
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Extracellular adenosine plays a key role in promoting bone tissue formation. Local delivery of adenosine could be an effective therapeutic strategy to harness the beneficial effect of extracellular adenosine on bone tissue formation following injury. Herein, we describe the development of an injectable in situ curing scaffold containing microgel-based adenosine delivery units. The two-component scaffold includes adenosine-loaded microgels and functionalized hyaluronic acid (HA) molecules. The microgels were generated upon copolymerization of 3-acrylamidophenylboronic acid (3-APBA)- and 2-aminoethylmethacrylamide (2-AEMA)-conjugated HA (HA-AEMA) in an emulsion suspension. The PBA functional groups were used to load the adenosine molecules. Mixing of the microgels with the HA polymers containing clickable groups, dibenzocyclooctyne (DBCO) and azide (HA-DBCO and HA-Azide), resulted in a 3D scaffold embedded with adenosine delivery units. Application of the in situ curing scaffolds containing adenosine-loaded microgels following tibial fracture injury showed improved bone tissue healing in a mouse model as demonstrated by the reduced callus size, higher bone volume, and increased tissue mineral density compared to those treated with the scaffold without adenosine. Overall, our results suggest that local delivery of adenosine could potentially be an effective strategy to promote bone tissue repair.