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1.
medRxiv ; 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-39040198

RESUMO

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.

2.
Musculoskelet Sci Pract ; 73: 103132, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39024739

RESUMO

BACKGROUND: In response to the COVID-19 pandemic, face-to-face consultations within healthcare settings were suspended. Remote consultations became crucial for managing musculoskeletal conditions alongside Patient Initiated Follow-ups, leading to the development of the DiAL programme at a large National Health Service Community Trust. Previous research has focused on quantitative data, little is known about staff experiences with this programme. OBJECTIVES: To explore the perceptions and opinions of physiotherapy staff using DiAL, in order to highlight the benefits and challenges of this service with identification of areas for future development. DESIGN: Qualitative focus groups. METHODS: Two virtual focus groups were conducted via Microsoft Teams, involving a purposive sample of physiotherapy staff in the musculoskeletal services known to have used DiAL. Thematic analysis was conducted. RESULTS: Ten clinicians participated in the study, generating two main themes: Clinician Autonomy and Institutional Needs. These themes encompassed several subthemes. CONCLUSIONS: Clinicians reported higher job satisfaction and improved accessibility for patients, attributing these positive outcomes to the autonomy and flexibility provided by the platform. While the programme met National Health Service targets for Patient Initiated Follow-ups, there was a desire for ongoing improvements and a recognition that previous audits failed to capture all the benefits. DiAL serves as a treatment choice, supporting evidence on the advantages of remote consultations and contributing to the National Health Services' goal of reducing its carbon footprint. There is a collective desire for the platform to continue with future recommendations including expanding its use and exploring additional audit metrics.

3.
Emerg Infect Dis ; 30(2): 358-362, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38270142

RESUMO

Using multipathogen PCR testing, we identified 195 students with adenovirus type 4 infections on a university campus in South Carolina, USA, during January-May 2022. We co-detected other respiratory viruses in 43 (22%) students. Continued surveillance of circulating viruses is needed to prevent virus infection outbreaks in congregate communities.


Assuntos
Infecções por Adenoviridae , Humanos , South Carolina/epidemiologia , Universidades , Surtos de Doenças , Estudantes
4.
J Surg Res ; 295: 175-181, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38029630

RESUMO

INTRODUCTION: Patient outcomes heavily rely on nutritional support. However, holding enteric feeds prior to surgical operations in critically ill patients is still a common practice in intensive critical units. Our objective is to describe the relationship between duration of nil per os (NPO) and respiratory outcomes in intubated, critically ill patients requiring operative intervention. METHODS: We conducted a retrospective analysis on intubated, critically ill patients who underwent operative intervention between January 1, 2016, and December 31, 2018, to investigate how the duration of NPO status may affect respiratory outcomes. We compared adverse respiratory events among patients who maintain NPO ≥6 h (NPO group) versus those who were NPO <6 h (non-NPO group) prior to surgery. RESULTS: Two hundred patients met inclusion criteria: 104 for NPO and 96 for non-NPO. Aspiration event was found in 5.8% of NPO patients and 7.3% in non-NPO patients, P = 0.66. Desaturation event was found in 16.3% for NPO and 14.6% in non-NPO, P = 0.73. Pneumonia was found in 18.3% of NPO patients and 19.8% in non-NPO patients, P = 0.78. Reintubated rates were 13.5% for NPO and 16.7% for non-NPO, P = 0.57. Median (range) hours of NPO for non-NPO was 1.0 h (0-3.0) and 13.0 h (6.0-20.0) for NPO, P < 0.05. CONCLUSIONS: For intubated, critically ill patients requiring operative intervention, there was no difference observed in adverse respiratory events between those kept NPO for 6 h or greater compared to those kept NPO for less than 6 h. Patients were commonly without enteric nutrition for periods of time much greater than the American Society of Anesthesia's recommended 6-h period.


Assuntos
Estado Terminal , Nutrição Enteral , Humanos , Estudos Retrospectivos , Estado Terminal/terapia , Nutrição Enteral/efeitos adversos , Fatores de Tempo
5.
Proc Biol Sci ; 290(2010): 20231458, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37909081

RESUMO

Parental care is considered crucial for the enhanced survival of offspring and evolutionary success of many metazoan groups. Most bryozoans incubate their young in brood chambers or intracoelomically. Based on the drastic morphological differences in incubation chambers across members of the order Cheilostomatida (class Gymnolaemata), multiple origins of incubation were predicted in this group. This hypothesis was tested by constructing a molecular phylogeny based on mitogenome data and nuclear rRNA genes 18S and 28S with the most complete sampling of taxa with various incubation devices to date. Ancestral character estimation suggested that distinct types of brood chambers evolved at least 10 times in Cheilostomatida. In Eucratea loricata and Aetea spp. brooding evolved unambiguously from a zygote-spawning ancestral state, as it probably did in Tendra zostericola, Neocheilostomata, and 'Carbasea' indivisa. In two further instances, brooders with different incubation chamber types, skeletal and non-skeletal, formed clades (Scruparia spp., Leiosalpinx australis) and (Catenicula corbulifera (Steginoporella spp. (Labioporella spp., Thalamoporella californica))), each also probably evolved from a zygote-spawning ancestral state. The modular nature of bryozoans probably contributed to the evolution of such a diverse array of embryonic incubation chambers, which included complex constructions made of polymorphic heterozooids, and maternal zooidal invaginations and outgrowths.


Assuntos
Briozoários , Invertebrados , Animais , Filogenia , Reprodução/genética
6.
Retrovirology ; 19(1): 28, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36514107

RESUMO

We present 109 near full-length HIV genomes amplified from blood serum samples obtained during early 1986 from across Uganda, which to our knowledge is the earliest and largest population sample from the initial phase of the HIV epidemic in Africa. Consensus sequences were made from paired-end Illumina reads with a target-capture approach to amplify HIV material following poor success with standard approaches. In comparisons with a smaller 'intermediate' genome dataset from 1998 to 1999 and a 'modern' genome dataset from 2007 to 2016, the proportion of subtype D was significantly higher initially, dropping from 67% (73/109), to 57% (26/46) to 17% (82/465) respectively (p < 0.0001). Subtype D has previously been shown to have a faster rate of disease progression than other subtypes in East African population studies, and to have a higher propensity to use the CXCR4 co-receptor ("X4 tropism"); associated with a decrease in time to AIDS. Here we find significant differences in predicted tropism between A1 and D subtypes in all three sample periods considered, which is particularly striking the 1986 sample: 66% (53/80) of subtype D env sequences were predicted to be X4 tropic compared with none of the 24 subtype A1. We also analysed the frequency of subtype in the envelope region of inter-subtype recombinants, and found that subtype A1 is over-represented in env, suggesting recombination and selection have acted to remove subtype D env from circulation. The reduction of subtype D frequency over three decades therefore appears to be a result of selective pressure against X4 tropism and its higher virulence. Lastly, we find a subtype D specific codon deletion at position 24 of the V3 loop, which may explain the higher propensity for subtype D to utilise X4 tropism.


Assuntos
Infecções por HIV , HIV-1 , Receptores CXCR4 , Tropismo Viral , Humanos , População Africana , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , Receptores CXCR4/genética , Uganda
7.
Viruses ; 14(8)2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-36016295

RESUMO

The Sustainable East Africa Research in Community Health (SEARCH) trial was a universal test-and-treat (UTT) trial in rural Uganda and Kenya, aiming to lower regional HIV-1 incidence. Here, we quantify breakthrough HIV-1 transmissions occurring during the trial from population-based, dried blood spot samples. Between 2013 and 2017, we obtained 549 gag and 488 pol HIV-1 consensus sequences from 745 participants: 469 participants infected prior to trial commencement and 276 SEARCH-incident infections. Putative transmission clusters, with a 1.5% pairwise genetic distance threshold, were inferred from maximum likelihood phylogenies; clusters arising after the start of SEARCH were identified with Bayesian time-calibrated phylogenies. Our phylodynamic approach identified nine clusters arising after the SEARCH start date: eight pairs and one triplet, representing mostly opposite-gender linked (6/9), within-community transmissions (7/9). Two clusters contained individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, both linked to intervention communities. The identification of SEARCH-incident, within-community transmissions reveals the role of unsuppressed individuals in sustaining the epidemic in both arms of a UTT trial setting. The presence of transmitted NNRTI resistance, implying treatment failure to the efavirenz-based antiretroviral therapy (ART) used during SEARCH, highlights the need to improve delivery and adherence to up-to-date ART recommendations, to halt HIV-1 transmission.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Fármacos Anti-HIV/uso terapêutico , Teorema de Bayes , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Inibidores da Transcriptase Reversa/uso terapêutico , Uganda/epidemiologia
8.
J Surg Res ; 279: 748-754, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35940051

RESUMO

INTRODUCTION: Due to the rarity of traumatic hemothorax in children, no studies have evaluated factors associated with successful video-assisted thoracoscopic surgery (VATS) as definitive management. METHODS: We conducted an exploratory cross-sectional analysis of pediatric patients in the Trauma Quality Programs database from 2008 to 2017 with traumatic hemothorax managed with primary VATS. Those with early resuscitative thoracotomy for cardiac arrest were excluded. We stratified patients by blunt or penetrating mechanism and estimated absolute differences (ADs) and 95% confidence intervals (CIs) to identify factors associated with successful VATS without conversion to thoracotomy or reoperation. RESULTS: A total of 293 patients were eligible. Among 184 penetrating injuries, 150 (82%) underwent successful VATS, 6 (3%) required reoperation, and 28 (15%) converted to thoracotomy. Diaphragmatic injuries (AD = -28, 95% CI = -46 to -10) and rib fractures (AD = 12, 95% CI = 1 to 23) had the strongest negative and positive associations (respectively) with successful VATS. There were 109 blunt injuries: 86 (79%) underwent successful VATS, 6 (6%) required reoperation, and 17 (16%) converted to thoracotomy. Moderate or severe head injury (AD = -15, 95% CI = -32 to 2), injury severity score >15 (AD = -19, 95% CI = -33 to -5), and the presence of diaphragmatic injury (AD = -38, 95% CI = -71 to -4) had the strongest negative associations with successful VATS. CONCLUSIONS: Some children with traumatic hemothorax can be successfully managed with VATS. For penetrating mechanism, diaphragmatic injuries were associated with less success, while rib fractures were associated with more success. For blunt mechanism, diaphragmatic injuries, injury severity score >15, or moderate or severe head injury were associated with less success.


Assuntos
Traumatismos Craniocerebrais , Fraturas das Costelas , Traumatismos Torácicos , Criança , Estudos Transversais , Hemotórax/etiologia , Hemotórax/cirurgia , Humanos , Tempo de Internação , Estudos Retrospectivos , Fraturas das Costelas/complicações , Traumatismos Torácicos/complicações , Traumatismos Torácicos/cirurgia , Cirurgia Torácica Vídeoassistida/efeitos adversos , Toracotomia/efeitos adversos
9.
J Surg Res ; 279: 299-303, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35802945

RESUMO

INTRODUCTION: The purpose of this study was to evaluate changes to acute pediatric surgical needs during the early phase of the SARS-Cov2 (COVID-19) pandemic. METHODS: We performed a retrospective cohort study of all in-hospital pediatric surgery consultations placed through the consult paging system at a single institution. We compared both median and absolute differences for emergency department (ED), operative, and hospital outcomes between March, April, and May of 2019 versus 2020. RESULTS: There were 225 in-hospital pediatric surgery consults in 2019 and 123 in 2020. Overall, mean age was 8.4-y (standard deviation = 6.4) and 60% were male. Initial vitals were similar between years and a similar proportion of patients underwent laboratory and imaging tests. In 2020, children spent a median of 1.1-h fewer in the ED (95% confidence interval = -2.2, -0.1) and 0.9-h fewer in the ED before surgical consultation (95% confidence interval = -1.5, -0.3) compared to 2019. Patients required significantly more procedures in the ED in 2020 (n = 16, 14.3%) than 2019 (n = 13, 6.2%) (P = 0.02), most commonly laceration repairs. In 2019, 46 children (20.4% of all consults in 2019) presented with appendicitis and 27 children (22.0% of all consults in 2020) in 2020. Complicated appendicitis was more common in 2020 (n = 12, 44.4%) than 2019 (n = 9, 19.6%) (P = 0.02). Two children (7.4%) were managed nonoperatively with a drain in 2020 compared to none in 2019 (P = 0.13). Median time from surgical consultation to surgery, median operative time, and median time to discharge was similar for children with appendicitis in both years. CONCLUSIONS: The early phase of the pandemic was associated with more efficient triaging in the ED, but more ED procedures and more complex surgical pathology.


Assuntos
Apendicite , COVID-19 , Apendicite/epidemiologia , Apendicite/cirurgia , COVID-19/epidemiologia , Criança , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pandemias , RNA Viral , Encaminhamento e Consulta , Estudos Retrospectivos , SARS-CoV-2
10.
Proc Natl Acad Sci U S A ; 119(19): e2108815119, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35500121

RESUMO

The prevailing abundance of full-length HIV type 1 (HIV-1) genome sequences provides an opportunity to revisit the standard model of HIV-1 group M (HIV-1/M) diversity that clusters genomes into largely nonrecombinant subtypes, which is not consistent with recent evidence of deep recombinant histories for simian immunodeficiency virus (SIV) and other HIV-1 groups. Here we develop an unsupervised nonparametric clustering approach, which does not rely on predefined nonrecombinant genomes, by adapting a community detection method developed for dynamic social network analysis. We show that this method (dynamic stochastic block model [DSBM]) attains a significantly lower mean error rate in detecting recombinant breakpoints in simulated data (quasibinomial generalized linear model (GLM), P<8×10−8), compared to other reference-free recombination detection programs (genetic algorithm for recombination detection [GARD], recombination detection program 4 [RDP4], and RDP5). When this method was applied to a representative sample of n = 525 actual HIV-1 genomes, we determined k = 29 as the optimal number of DSBM clusters and used change-point detection to estimate that at least 95% of these genomes are recombinant. Further, we identified both known and undocumented recombination hotspots in the HIV-1 genome and evidence of intersubtype recombination in HIV-1 subtype reference genomes. We propose that clusters generated by DSBM can provide an informative framework for HIV-1 classification.


Assuntos
HIV-1 , HIV-1/genética , Recombinação Genética
11.
J Laparoendosc Adv Surg Tech A ; 32(5): 561-565, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35501952

RESUMO

Introduction: While laparoscopy is now widely accepted for inguinal hernia repair in infants, it traditionally has required general anesthesia. We sought to evaluate the safety of laparoscopic inguinal hernia repair in infants under spinal anesthesia. Materials and Methods: We performed a retrospective cohort study of all inguinal hernia repairs at a single institution between December 2011 and June 2019 in patients younger than 6 months of age. Four groups were compared: laparoscopic under general anesthesia, laparoscopic with spinal anesthesia, open with spinal anesthesia, and open under general anesthesia. Main outcome measures include operative time, cost, and postoperative outcomes. These were assessed using Kruskal-Wallis median comparison. Results: Of the 226 patients meeting inclusion criteria, 54% (122/226) of patients underwent general anesthesia, while 46% (104/226) had spinal. When compared to general anesthesia, spinal anesthesia was associated with significantly shorter procedure times (P < .01) and lower cost (P < .01) for both open and laparoscopic approaches. Complications were few and underpowered to calculate significance across each group. Conclusions: Laparoscopic inguinal hernia repair can be safely performed in infants under spinal anesthesia without significant compromise of early perioperative outcomes. Advantages may include shorter procedure time and lower cost.


Assuntos
Raquianestesia , Hérnia Inguinal , Laparoscopia , Hérnia Inguinal/cirurgia , Herniorrafia/métodos , Humanos , Lactente , Recém-Nascido , Laparoscopia/métodos , Ligadura , Estudos Retrospectivos , Resultado do Tratamento
12.
Orthop J Sports Med ; 10(4): 23259671211041400, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35400136

RESUMO

Background: A subset of patients with femoroacetabular impingement (FAI) fail arthroscopic management. It is not clear which patients will fail surgical management; however, several surgical and patient factors, such as type of procedure and age, are thought to be important predictors. Purpose: This time-to-event analysis with a 27-month follow-up analysis compared the effect of (1) arthroscopic osteochondroplasty with or without labral repair versus (2) arthroscopic lavage with or without labral repair on the time to reoperation in adults aged 18 to 50 years with FAI. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Eligible participants had been randomized in a previous study trial to a treatment of arthroscopic osteochondroplasty or arthroscopic lavage with or without labral repair. Using the comprehensive data set from the Multinational Femoroacetabular Impingement Randomized controlled Trial, all reoperations until 27 months after surgery were identified. The analysis was conducted using a Cox proportional hazards model, with percentage of patients with a reoperation evaluated in a time-to-event analysis as the outcome. The independent variable was the procedure, with age and impingement subtype explored as potential covariates. The effects from the Cox model were expressed as the hazard ratio (HR). All tests were 2-sided, with an alpha level of .05. Results: A total of 108 patients in the osteochondroplasty group and 106 patients in the lavage group were included. The mean age of the patients included in the study was 36 ± 8.5 years. Overall, 27 incident reoperations were identified within the 27-month follow-up, with an incidence rate of 6 per 100 person-years. Within the osteochondroplasty group, 8 incident reoperations were identified (incidence rate, 3.4 per 100 person-years), while within the lavage group, 19 incident reoperations were identified (incidence rate, 8.7 per 100 person-years). The hazard of reoperation for patients undergoing osteochondroplasty was 40% of that of patients undergoing lavage (HR, 0.40 [95% CI, 0.17-0.91] P = .029). Conclusion: This study demonstrated that for adults between the ages of 18 and 50 years with FAI, arthroscopic osteochondroplasty was associated with a 2.5-fold decrease in the hazard of reoperation at any point in time compared with arthroscopic lavage. Registration: NCT01623843 (ClinicalTrials.gov identifier).

13.
J Surg Res ; 269: 83-93, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534856

RESUMO

BACKGROUND: Few studies have identified factors associated with successful VATS or thoracotomy as the initial operative strategy among patients with traumatic hemothorax. MATERIAL AND METHODS: We performed an exploratory analysis using the 2008 to 2017 TQP database. We identified all patients aged 18 to 89 years with traumatic hemothorax who were treated with tube thoracostomy alone in the first 24-hours of admission, followed by VATS or thoracotomy. Logistic regression was used to identify factors associated with successful VATS (no conversion or reoperation) or thoracotomy (no reoperation) as the initial operative strategy. RESULTS: Among 2052 patients managed with initial VATS after chest tube drainage, 1710 (83%) were successful, while 263 (13%) were converted to thoracotomy and 79 (4%) required reoperation. On multivariable analysis, poor GCS (OR = 0.96 [95% CI = 0.94-0.99]), major injury (OR = 0.69 [95% CI = 0.53-0.90]), and diaphragmatic injury (OR = 0.42 [95% CI = 0.30-0.60]) were associated with lower odds of successful VATS, while rib fractures (OR=1.29 [95% CI=1.01-1.66]) were associated with higher odds of success of the initial operative plan. Among 3486 patients initially managed with thoracotomy after drainage with tube thoracostomy, 3118 (89.4%) were successful, while 11% (n = 368) required reoperation. Multivariable analysis revealed that major injury (OR = 0.68 [95% CI = 0.50-0.92]), blunt mechanism (OR = 0.63 [95% CI = 0.50-0.78]), and diaphragmatic injury (OR = 0.67, 95% CI = 0.53-0.84]) were associated with lower odds of successful thoracotomy as the initial operative plan. CONCLUSIONS: More severe injuries and diaphragmatic injuries have lower odds of successful of VATS or thoracotomy as the initial operative management strategy among patients with traumatic hemothorax. Rib fractures may be associated with higher odds of success of VATS as the initial management strategy.


Assuntos
Traumatismos Torácicos , Cirurgia Torácica Vídeoassistida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Hemotórax/etiologia , Hemotórax/cirurgia , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Traumatismos Torácicos/complicações , Traumatismos Torácicos/cirurgia , Cirurgia Torácica Vídeoassistida/efeitos adversos , Toracotomia/efeitos adversos , Resultado do Tratamento , Adulto Jovem
14.
J Laparoendosc Adv Surg Tech A ; 31(12): 1455-1459, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34783264

RESUMO

Background: When the disposable arthroscopic banana knife (Linvatec, Largo, FL) became unavailable, many pediatric surgeons adapted the use of spatula tip cautery for laparoscopic pyloromyotomy; however, reusable arthroscopic knives remain readily available and are well suited to the procedure. Methods: We compared laparoscopic pyloromyotomy with a reusable arthroscopic banana knife (Sklar, West Chester, PA; catalog no. 45-6050) to those using spatula tip cautery at a single institution between September 1, 2012, and December 31, 2019. Mann-Whitney U test was used to compare operative time, room time, and time to discharge between groups. Results: Overall, 109 patients underwent pyloromyotomy for hypertrophic pyloric stenosis during the study time period. Of these, 12 were open and one was undertaken with the Storz pyloromyotomy knife, so these were excluded. A total of 74 (77.1%) laparoscopic cases with spatula tip cautery and 22 (22.9%) with the banana knife were included. Mean age at the time of surgery was ∼37 days. The majority of patients in each group were white, male, and full term. The most common comorbid conditions were reactive airway disease and neonatal abstinence syndrome. There were no significant differences in operative time (P = .61), room time (P = .41), or time from surgery to discharge (P = .26) between procedures using the banana knife and those using the cautery spatula tip. There were no perforations or recurrences. Conclusion: Our findings suggest that the reusable banana knife is a safe and effective alternative to spatula tip cautery for laparoscopic pyloromyotomy, with no difference in operative time, time from surgery to discharge, or complications.


Assuntos
Laparoscopia , Musa , Estenose Pilórica Hipertrófica , Piloromiotomia , Criança , Humanos , Lactente , Recém-Nascido , Masculino , Estenose Pilórica Hipertrófica/cirurgia , Piloro/cirurgia
15.
Elife ; 102021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378534

RESUMO

Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.


Assuntos
Anticorpos Biespecíficos/efeitos adversos , Dispositivos Lab-On-A-Chip/estatística & dados numéricos , Linfócitos T/imunologia , Animais , Feminino , Células HEK293 , Células HeLa , Humanos , Imunoterapia/métodos , Camundongos
16.
Surg Obes Relat Dis ; 17(6): 1146-1151, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33839047

RESUMO

BACKGROUND: Bariatric surgery is now accepted for adolescents; however, we may need to improve access to surgery for this vulnerable age group. OBJECTIVES: To compare the demographic characteristics and short-term safety outcomes of adolescents, college-aged individuals, and young adults who have had metabolic and bariatric surgery. SETTING: Bariatric surgery centers. METHODS: Patients aged 13-25 years in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database from 2015-2018 with a Current Procedural Terminology (CPT) code for sleeve gastrectomy (SG) or gastric bypass (GB) were included. Patients were stratified by operation and analyzed by age: adolescents (13-17 yr), college-aged (18-21 yr), and young adults (22-25 yr). RESULTS: Of the 760,076 patients in the database, 1047 adolescents (.1%), 10,429 college-aged individuals (1.4%), and 24,841 young adults (3.8%) underwent SG or GB. The majority of patients in each group were female and white. Diabetes was most common among adolescents, hypertension among college-aged individuals. The most prevalent co-morbidity among young adults was diabetes. Preoperative BMI was 47 across all age strata. SG was performed in 27,292 patients: 879 (3.2%) adolescents, 7955 (29.2%) college-aged, and 18,447 (67.6%) young adults. Postoperative complications occurred in approximately 1% of individuals and were similar between age groups (P = .23). A total of 8292 patients underwent GB: 146 (1.8%) adolescents, 2207 (26.6%) college-aged, and 5939 (71.6%) young adults. There was no difference in 30-day complication rates between age groups (P = .32). CONCLUSIONS: There may be a disparity in access to metabolic and bariatric surgery among adolescents, particularly for racial and ethnic minorities; however, these procedures are likely safe in adolescents as young as 13.


Assuntos
Cirurgia Bariátrica , Derivação Gástrica , Laparoscopia , Obesidade Mórbida , Adolescente , Feminino , Gastrectomia , Humanos , Masculino , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
Am J Sports Med ; 49(1): 25-34, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32970955

RESUMO

BACKGROUND: Femoroacetabular impingement (FAI) is a condition known to cause hip pain in young adults. PURPOSE: To evaluate the efficacy of the surgical correction of FAI via arthroscopic osteochondroplasty with or without labral repair compared with arthroscopic lavage of the hip joint with or without labral repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 220 male and female participants aged 18 to 50 years with nonarthritic FAI suitable for surgical treatment were recruited for the trial at 10 clinical centers in Canada, Finland, and Denmark between October 2012 and November 2017, of whom 214 were included in the final analysis. In the osteochondroplasty group, cam- and/or pincer-type lesions were resected using fluoroscopic guidance. In the lavage group, the joint was washed out with 3 L of normal saline. Surgeons were instructed to repair the labrum in both groups if it was mechanically unstable once probed, showing visible displacement or chondrolabral separation. The primary outcome was patient-reported pain (using the 100-point visual analog scale [VAS]) at 12 months. Secondary outcomes included hip function (Hip Outcome Score [HOS] and International Hip Outcome Tool), physical and mental health (12-Item Short Form Health Survey), and health utility (EuroQol-5 Dimensions) at 12 months as well as any reoperations and other hip-related adverse events at 24 months. RESULTS: At 12 months, there was no difference in pain (VAS) between the groups (mean difference [MD], 0.11 [95% CI, -7.22 to 7.45]; P = .98). Also, 88.3% (189/214) of participants had a labral tear, of which 60.3% were repaired. For the secondary outcomes, there were no significant differences between treatment groups, with the exception of the HOS activities of daily living domain in which lavage showed significant improvement compared with osteochondroplasty (MD, -5.03 [95% CI, -10.40 to -0.03]; P = .049). By 24 months, there were significantly fewer reoperations reported in the osteochondroplasty group (8/105) than the lavage group (19/104) (odds ratio, 0.37 [95% CI, 0.15-0.89]; P = .026). The primary reasons for a reoperation included hip pain (15/27; 55.6%) and a reinjury of the labrum (11/27; 40.7%). CONCLUSION: Both the osteochondroplasty and the lavage groups with or without labral repair for FAI had significantly improved pain or function significantly at 1 year. By 2 years, the reoperation rate was significantly lower in the osteochondroplasty group. REGISTRATION: NCT01623843 (ClinicalTrials.gov identifier).


Assuntos
Impacto Femoroacetabular , Atividades Cotidianas , Adolescente , Adulto , Artroscopia , Canadá , Feminino , Impacto Femoroacetabular/cirurgia , Finlândia , Seguimentos , Articulação do Quadril , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Virus Evol ; 6(1): veaa004, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32395255

RESUMO

Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for 50 years, frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants in this population and the location of breakpoints along the genome. As part of the PANGEA-HIV consortium, 1,472 consensus genome sequences over 5 kb have been obtained from 1,857 samples collected by the MRC/UVRI & LSHTM Research unit in Uganda, 465 (31.6 per cent) of which were near full-length sequences (>8 kb). Using the subtyping tool SCUEAL, we find that of the near full-length dataset, 233 (50.1 per cent) genomes contained only one subtype, 30.8 per cent A1 (n = 143), 17.6 per cent D (n = 82), and 1.7 per cent C (n = 8), while 49.9 per cent (n = 232) contained more than one subtype (including A1/D (n = 164), A1/C (n = 13), C/D (n = 9); A1/C/D (n = 13), and 33 complex types). K-means clustering of the recombinant A1/D genomes revealed a section of envelope (C2gp120-TMgp41) is often inherited intact, whilst a generalized linear model was used to demonstrate significantly fewer breakpoints in the gag-pol and envelope C2-TM regions compared with accessory gene regions. Despite similar recombination patterns in many recombinants, no clearly supported circulating recombinant form (CRF) was found, there was limited evidence of the transmission of breakpoints, and the vast majority (153/164; 93 per cent) of the A1/D recombinants appear to be unique recombinant forms. Thus, recombination is pervasive with clear biases in breakpoint location, but CRFs are not a significant feature, characteristic of a complex, and diverse epidemic.

19.
Surg Endosc ; 34(5): 2204-2210, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385075

RESUMO

INTRODUCTION: Jejunojejunal intussusception after Roux-en-Y gastric bypass (RYGBP) for morbid obesity is a rare but potentially catastrophic complication. There are limited data regarding the incidence of intussusception and the different surgical options for management of this disease. METHODS: This is a retrospective review of all patients that underwent RYGBP and subsequently developed intussusception at the jejunojejunostomy. Data were collected between 1/1/2008 and 5/31/2018 and included demographics, details related to the index procedure, presentation, and management of intussusception. Perioperative outcomes and complications were also collected. RESULTS: 665 patients underwent RYGBP. A total of 34 patients developed intussusception, with 31 (4.7%) of them having undergone RYGBP in our hospital. Demographics included age, gender, and BMI at both the index surgery and at the time of intussusception. The jejunojejunostomy was created during RYGBP using a linear stapler in all patients with 64.5% of them achieving a length of 90 mm. All intussuscepted patients presented acutely with abdominal pain. All but one patient required surgical intervention. 42.4% of the patients were found to have intraoperative intussusception which appeared to be retrograde in 78.6% of them. Reduction followed by enteropexy or just enteropexy was performed in 20 patients (60.6%) that required surgery. No immediate post-operative complications were noted but 8 patients (26.5%) had recurrence of intussusception requiring another surgical intervention. In the reoperated group, 75% of the patients were treated with reduction followed by enteropexy or just enteropexy. CONCLUSIONS: This is the largest case series describing jejunojejunal intussusception following RYGBP. All patients that developed intussusception had jejunojejunostomy length greater than 60 mm. The most commonly performed surgical repair was reduction of the intussuscepted segment (if present) followed by enteropexy. Jejunojejunostomy length greater than 60 mm might be associated with the occurrence of intussusception and could explain the higher incidence noted in our series. Minimal intervention with enteropexy can offer effective treatment for most patients.


Assuntos
Derivação Gástrica/métodos , Intussuscepção/etiologia , Intussuscepção/terapia , Doenças do Jejuno/cirurgia , Obesidade Mórbida/cirurgia , Adulto , Feminino , Humanos , Incidência , Masculino , Estudos Retrospectivos , Resultado do Tratamento
20.
Am J Surg ; 220(1): 132-134, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703837

RESUMO

BACKGROUND: Leukopenic patients have historically been considered poor surgical candidates due to a perceived increase in operative morbidity and mortality. METHODS: Retrospective cohort study using the NSQIP database to identify adult patients who received chemotherapy for malignancy within 30-days prior to elective or emergent abdominal surgery between 2008 and 2011. Leukopenia was defined as < 4000 WBC/mm3 within 2-days prior to surgery. Multiple logistic regression assessed if leukopenia was associated with morbidity and mortality. RESULTS: Of the 4369 patients included, 20.2% had preoperative leukopenia. Emergency cases comprised 36.2% of cases. Overall 30-day mortality was 12.2% and 30-day composite morbidity was 29.8%. After controlling for significant confounders, including emergency status, leukopenia was not significantly associated with either postoperative mortality (p = 0.14) or morbidity (p = 0.17). CONCLUSIONS: Our study suggests that in cancer patients undergoing chemotherapy, leukopenia is not associated with morbidity or mortality and should not influence operative planning in either the elective or emergent setting.


Assuntos
Procedimentos Cirúrgicos Eletivos/métodos , Emergências , Leucopenia/epidemiologia , Neoplasias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Comorbidade , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
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