RESUMO
BACKGROUND: Deep inferior epigastric perforator (DIEP) surgery is one of the most difficult breast reconstruction techniques available, both in terms of operating complexity and patient recovery. Enhanced recovery after surgery (ERAS) pathways were recently introduced in numerous subspecialties to reduce recovery time, patient pain, and cost by providing multimodal perioperative care. Plastic surgery has yet to widely integrate ERAS with DIEP reconstruction, mostly due to insufficient data on patient outcomes with this combined approach. METHODS: Five major medical databases were queried using predetermined search criteria according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Statistical analysis was performed using Cochrane's RevMan (v5.4). RESULTS: A total of 466 articles were identified. A total of 14 studies were included in the review with a combined sample of 2102 patients. Eight studies were included in the meta-analysis with a combined sample of 1679 patients. On average, the included studies utilized 11.69 of 18 suggested protocols for ERAS with breast reconstruction. Our primary outcome, length of stay, was reduced by a mean of 1.12 (95% confidence interval [CI] [-1.30, -0.94], n = 1627, p < 0.001) days in the ERAS group. Postoperative oral morphine equivalents (OME) were also reduced in the ERAS group by 104.02 (95% CI [-181.43, -26.61], n = 545, p = 0.008) OME. The ERAS group saw a significant 3.54 (95% CI [-4.43, -2.65], n = 527, p < 0.001) standardized mean difference cost reduction relative to the control groups. The surgery time was reduced by 60.46 (95% CI [-125, 4.29], n = 624, p < 0.07) min, although this was not statistically significant. CONCLUSIONS: The ERAS pathway in DIEP breast reconstruction is consistently associated with reduced hospital stay, opioid use, and patient cost. Moreover, there appears to be no evidence of serious adverse outcomes associated with the application of the ERAS protocol.
Assuntos
Recuperação Pós-Cirúrgica Melhorada , Mamoplastia , Retalho Perfurante , Humanos , Mamoplastia/métodos , Mama , Assistência PerioperatóriaAssuntos
Medicina Geral , Ginecologia , Internato e Residência , Obstetrícia , Feminino , Gravidez , Humanos , Ginecologia/educação , Obstetrícia/educação , FertilidadeRESUMO
The majority of out-of-hours cases relate to neurological, chest, and gastrointestinal pathologies with acute vascular cases being encountered less commonly. Trainees and exposure of non-vascular/interventional radiology (IR) consultants to angiographic imaging is often limited in working hours and this may lead to reporting on-call cases outside of normal daytime practice. In a recent local review, a number on-call vascular studies were found to contain a number of vascular-related discrepancies. Vascular reporting is a complex subspecialty, which comprises many clear diagnoses (large vessel occlusions, large vessel aneurysms, or dissections); however, also several subtle and complex abnormalities. These more subtle abnormalities, at times, require dedicated vascular specialist review to ensure subtle findings are communicated appropriately to the clinical team. The recent increased complexity of endovascular treatments and their complications has also provided further challenge for the non-specialist reporter. Similarly, improved imaging techniques have allowed for non-obvious but significant findings that may require urgent management, such as small aneurysms and dissection flaps. We will review a range of key vascular findings that demonstrate learning opportunities, particularly within the acute and on-call settings. These will include gastrointestinal haemorrhage, subtle aortic pathologies, head and neck vascular emergencies, small to mid-sized vessel injuries and imaging of post-procedural complications. Educational hints and tips will be provided to enable learning from mistakes encountered by trainees and non-vascular specialist radiologists in the on-call or urgent reporting settings, and these will be reviewed with reference to the literature.
Assuntos
Plantão Médico , Vasos Sanguíneos/anormalidades , Erros de Diagnóstico , Doenças Vasculares/diagnóstico por imagem , Dissecção Aórtica/diagnóstico por imagem , Falso Aneurisma/diagnóstico por imagem , Aorta Torácica/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Artéria Basilar/diagnóstico por imagem , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/lesões , Comunicação , Emergências , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Hemorragia Gastrointestinal/diagnóstico por imagem , Humanos , Complicações Pós-Operatórias/diagnóstico por imagem , Radiologia Intervencionista , Artéria Vertebral/diagnóstico por imagemRESUMO
The clinical use of intracytoplasmic sperm injection (ICSI) in horses usually involves the transfer of embryos into recipient mares, resulting in substantial cost increases. This is essential when subfertile mares are oocyte donors; but some donors are fertile, with ICSI compensating for limited or poor-quality spermatozoa. Fertile oocyte donors could carry pregnancies, eliminating the need for a recipient. We assessed the potential of using oocyte donors as recipients for their own ICSI-produced embryos during the same cycle. Donors in oestrus and with large dominant follicles were administered ovulation-inducing compounds to cause follicle and oocyte maturation. Maturing oocytes were collected, cultured and fertilised using ICSI. At 6 or 7 days after ICSI, developing blastocysts were transferred into respective donors' uteri, and pregnancy rates were determined. Twenty follicles were aspirated from nine mares and 12 oocytes were collected. After ICSI, 10 of the 12 oocytes (83%) cleaved, and eight (67% of injected oocytes) developed into blastocysts for transfer. Five pregnancies resulted from the eight transferred embryos (pregnancy rate 62% per embryo and 42% per sperm-injected oocyte). Following this synchronisation regime, ICSI-produced embryos can be transferred into oocyte donors' uteri during the same cycle, allowing donors to carry pregnancies after assisted fertilisation.
Assuntos
Transferência Embrionária , Ciclo Estral/fisiologia , Cavalos , Injeções de Esperma Intracitoplásmicas , Doadores de Tecidos , Animais , Técnicas de Cultura Embrionária/veterinária , Transferência Embrionária/métodos , Transferência Embrionária/veterinária , Embrião de Mamíferos , Feminino , Cavalos/embriologia , Cavalos/fisiologia , Infertilidade/terapia , Infertilidade/veterinária , Masculino , Gravidez , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas/veterinária , Útero/fisiologiaRESUMO
Two-dimensional mixtures of dipolar colloidal particles with different dipole moments exhibit extremely rich self-assembly behaviour and are relevant to a wide range of experimental systems, including charged and super-paramagnetic colloids at liquid interfaces. However, there is a gap in our understanding of the crystallization of these systems because existing theories such as integral equation theory and lattice sum methods can only be used to study the high temperature fluid phase and the zero-temperature crystal phase, respectively. In this paper we bridge this gap by developing a density functional theory (DFT), valid at intermediate temperatures, in order to study the crystallization of one and two-component dipolar colloidal monolayers. The theory employs a series expansion of the excess Helmholtz free energy functional, truncated at second order in the density, and taking as input highly accurate bulk fluid direct correlation functions from simulation. Although truncating the free energy at second order means that we cannot determine the freezing point accurately, our approach allows us to calculate ab initio both the density profiles of the different species and the symmetry of the final crystal structures. Our DFT predicts hexagonal crystal structures for one-component systems, and a variety of superlattice structures for two-component systems, including those with hexagonal and square symmetry, in excellent agreement with known results for these systems. The theory also provides new insights into the structure of two-component systems in the intermediate temperature regime where the small particles remain molten but the large particles are frozen on a regular lattice.
RESUMO
Our objective of this study was to explore the bacterial microbiome in fresh or fresh-frozen adult Amblyomma maculatum (Gulf Coast ticks) using extracts enriched for microbial DNA. We collected 100 questing adult A. maculatum, surface disinfected them, and extracted DNA from individual ticks collected the same day or after storage at -80⯰C. Because only extracts with microbial DNA concentrations above 2â¯ng/µL were considered suitable for individual analysis, we expected fewer samples to meet these requirements. Of individual ticks extracted, 48 extracts met this minimum concentration. We pooled 20 additional extracts that had lower concentrations to obtain seven additional pools that met the minimum DNA concentration. Libraries created from these 55 samples were sequenced using an Illumina MiSeq platform, and data sets were analyzed using QIIME to identify relative abundance of microorganisms by phylum down to genus levels. Proteobacteria were in greatest abundance, followed by Actinobacteria, Firmicutes, and Bacteroidetes, at levels between 1.9% and 6.4% average relative abundance. Consistent with the Francisella-like endosymbiont known to be present in A. maculatum, the genus Francisella was detected at highest relative abundance (72.9%; SE 0.02%) for all samples. Among the top ten genera identified (relative abundanceâ¯≥â¯0.5%) were potential extraction kit contaminants, Sphingomonas and Methylobacterium, the soil bacterium Actinomycetospora, and the known A. maculatum-associated genus, Rickettsia. Four samples had Rickettsia at greater than 1% relative abundance, while nine additional samples had Rickettsia at low (0.01-0.04%) relative abundance. In this study, we used the entire microbe-enriched DNA extract for whole ticks for microbiome analysis. A direct comparison of the microbiome in microbe-enriched DNA and total genomic DNA extracts from halves of the same tick would be useful to determine the utility of this extraction method in this system. We anticipate that future tick microbiome studies will be valuable to explore the influence of microbial diversity on pathogen maintenance and transmission, and to evaluate niche-specific microbiomes within individual tick tissues.
Assuntos
Ixodidae/microbiologia , Microbiota/genética , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Animais , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Francisella/genética , Francisella/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Mississippi/epidemiologia , Filogenia , Proteobactérias/genética , Proteobactérias/isolamento & purificação , Rickettsia/genética , Infestações por Carrapato/epidemiologia , Extratos de TecidosRESUMO
Cyclosporine and aspirin are routinely used in combination to treat immune-mediated hemolytic anemia (IMHA) in dogs. Cyclosporine is a potent immunosuppressive agent that targets T cell production of the cytokines IL-2 and IFN-γ. Low-dose aspirin is often used to inhibit platelet function in dogs with IMHA, since these animals are prone to life-threatening thromboembolic disease. In rodents and humans, aspirin and cyclosporine have both been shown to variably affect T cell cytokine production, and also numbers of circulating regulatory T cells (Tregs). In dogs, it has not yet been determined if concurrent aspirin alters the effects of cyclosporine on T-cell cytokine expression, or if either drug influences Treg numbers. In a crossover study, seven healthy young adult dogs were given either oral high-dose cyclosporine (10â¯mg/kg Q12â¯h), oral low-dose aspirin (1â¯mg/kg Q24â¯h), oral high-dose aspirin (10â¯mg/kg Q12â¯h), or combined low-dose aspirin with cyclosporine, each for 8â¯days, with a washout of at least 2 weeks after each treatment. Activated T cell cytokine expression (IL-2 & IFN-γ) and percent CD4â¯+â¯CD25â¯+â¯FOXP3+ Tregs were evaluated using flow cytometry, both prior to and on the last day of treatment. The difference between pre- and post-treatment values for each group, as well as the difference between treatment groups, was evaluated. Cyclosporine significantly decreased IL-2 and IFN-γ expression when used alone or in combination with low-dose aspirin. High-dose aspirin, but not low-dose aspirin, also significantly decreased IL-2 expression, although the decrease was not as marked as that seen with cyclosporine alone or in combination with aspirin. Neither low-dose nor high-dose aspirin significantly affected IFN-γ expression. No drug or drug combination affected Treg numbers. Low-dose aspirin given with cyclosporine creates the same degree of T-cell cytokine suppression as does cyclosporine alone, suggesting that the two drugs can be used concurrently without significantly altering the immunosuppressive mechanism of action of cyclosporine.
Assuntos
Aspirina/farmacologia , Ciclosporina/farmacologia , Interferon gama/imunologia , Interleucina-2/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Administração Oral , Anemia Hemolítica/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Estudos Cross-Over , Ciclosporina/administração & dosagem , Cães , Citometria de Fluxo , Imunidade Celular , Imunossupressores/farmacologia , Ativação Linfocitária , Linfócitos T Reguladores/imunologiaRESUMO
Ventilatory acclimatization to hypoxia involves an increase in the acute hypoxic ventilatory response that is blocked by non-steroidal anti-inflammatory drugs administered during sustained hypoxia. We tested the hypothesis that inflammatory signals are necessary to sustain ventilatory acclimatization to hypoxia once it is established. Adult, rats were acclimatized to normoxia or chronic hypoxia (CH, [Formula: see text] =70Torr) for 11-12days and treated with ibuprofen or saline for the last 2days of hypoxia. Ventilation, metabolic rate, and arterial blood gas responses to O2 and CO2 were not affected by ibuprofen after acclimatization had been established. Immunohistochemistry and image analysis showed acute (1h) hypoxia activated microglia in a medullary respiratory center (nucleus tractus solitarius, NTS) and this was blocked by ibuprofen administered from the beginning of hypoxic exposure. Microglia returned to the control state after 7days of CH and were not affected by ibuprofen administered for 2 more days of CH. In contrast, NTS astrocytes were activated by CH but not acute hypoxia and activation was not reversed by administering ibuprofen for the last 2days of CH. Hence, ibuprofen cannot reverse ventilatory acclimatization or astrocyte activation after they have been established by sustained hypoxia. The results are consistent with a model for microglia activation or other ibuprofen-sensitive processes being necessary for the induction but not maintenance of ventilatory acclimatization to hypoxia.
Assuntos
Aclimatação/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Ibuprofeno/farmacologia , Ventilação/métodos , Análise de Variância , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipóxia/patologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Neuroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Centro Respiratório/efeitos dos fármacos , Núcleo Solitário/patologiaRESUMO
BACKGROUND: Synbiotics often are prescribed to limit antibiotic-associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking. OBJECTIVE: To determine whether synbiotic co-administration mitigates AAGS in healthy research cats treated with clindamycin. ANIMALS: 16 healthy research cats. METHODS: A randomized, double-blinded, placebo-controlled, 2-way, 2-period, crossover study with a 6-week washout was performed. Each study period consisted of a 1-week baseline and a 3-week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant. RESULTS: Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F-value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F-value = 31.1, P < 0.01) despite period effects (F-value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F-value = 17.9, P < 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic-associated diarrhea.
Assuntos
Antibacterianos/efeitos adversos , Doenças do Gato/induzido quimicamente , Clindamicina/efeitos adversos , Gastroenteropatias/veterinária , Simbióticos , Animais , Doenças do Gato/prevenção & controle , Gatos , Estudos Cross-Over , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/prevenção & controle , Masculino , Simbióticos/administração & dosagem , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/veterináriaRESUMO
The tribology between biphasic materials is challenging to predict and interpret due to the interrelationship between mechanical properties, microstructure and movement of the fluid phase contained within. A new approach is presented to deconvolute these effects for cellulose hydrogels, which have a fibrous network that is akin to the microstructure of articular cartilage and plant cell walls. This is achieved by developing a tribo-rheological technique that uniquely incorporates in situ mechanical characterisation (compression-relaxation and small amplitude oscillatory shear) immediately prior to measuring the tribological response between pairs of hydrogels. A radial pressure gradient is generated upon compression-relaxation of the poroelastic hydrogels that results in a non-uniform film thickness at the interface between them. Simulations of this process show that contact between gels occurs in an outer annulus region. Accounting for the predicted contact area between hydrogels varying in cellulose density and pectin solution viscosity causes measured tribology data to collapse onto a single curve; the apparent static friction between hydrogel tribopairs increases with the storage modulus of the hydrogels according to a power law with exponent 0.67. The method is used to compare the influence of plant cell wall polysaccharides, xyloglucan and arabinoxylan, on the interactive forces between cellulose fibres; xyloglucan is found to reduce the static friction between the hydrogels while arabinoxylan had no significant effect. The methodologies presented should provide a new framework for studying the friction between gels and other biphasic soft materials and polymeric surface films.
RESUMO
BACKGROUND: Storage of canine packed red blood cells (pRBCs) can increase erythrocyte phosphatidylserine (PS) expression and eicosanoid concentrations. HYPOTHESIS/OBJECTIVES: To determine the effects of leukoreduction on erythrocyte PS expression and eicosanoid concentrations in stored units of canine pRBCs. Our hypothesis was that leukoreduction would decrease PS expression and eicosanoid concentrations. ANIMALS: Eight healthy dogs. METHODS: In a cross-over study, units of whole blood were leukoreduced (LR) or non-LR and stored (10 and 21 days) as pRBCs. Samples were collected at donation, and before and after a simulated transfusion. PS expression was measured by flow cytometry, and concentrations of arachidonic acid (AA), prostaglandin F2α (PGF2α ), prostaglandin E2 (PGE2 ), prostaglandin D2 (PGD2 ), thromboxane B2 (TXB2 ), 6-keto-prostaglandin F1α (6-keto-PGF1α ), and leukotriene B4 (LTB4 ) were quantified by liquid chromatography-mass spectrometry. RESULTS: There was no change in PS expression during leukoreduction, storage, and simulated transfusion for non-LR and LR units. Immediately after leukoreduction, there was a significant increase in TXB2 and PGF2α concentrations, but during storage, these eicosanoids decreased to non-LR concentrations. In both LR and non-LR units, 6-keto-PGF1α concentrations increased during storage and simulated transfusion, but there was no difference between unit type. There was no difference in AA, LTB4 , PGE2 , and PGD2 concentrations between unit types. CONCLUSIONS AND CLINICAL IMPORTANCE: Leukoreduction, storage, and simulated transfusion do not alter erythrocyte PS expression. Leukoreduction causes an immediate increase in concentrations of TXB2 and PGF2α , but concentrations decrease to non-LR concentrations with storage. Leukoreduction does not decrease the accumulation of 6-keto-PGF1α during storage.
Assuntos
Preservação de Sangue/veterinária , Eicosanoides/sangue , Procedimentos de Redução de Leucócitos/veterinária , Fosfatidilserinas/sangue , Animais , Estudos Cross-Over , Cães , Transfusão de Eritrócitos/veterinária , Eritrócitos/metabolismo , Feminino , Citometria de Fluxo/veterinária , MasculinoRESUMO
Amblyomma maculatum Koch (Acari: Ixodidae), the primary vector for Rickettsia parkeri, may also be infected with a rickettsia of unknown pathogenicity, "Candidatus Rickettsia andeanae." Infection rates with these rickettsiae vary geographically, and coinfected ticks have been reported. In this study, infection rates of R. parkeri and "Ca. R. andeanae" were evaluated, and rickettsial DNA levels quantified, in 335 questing adult A. maculatum collected in 2013 (n = 95), 2014 (n = 139), and 2015 (n = 101) from Oktibbeha County, MS. Overall infection rates of R. parkeri and "Ca. R. andeanae" were 28.7% and 9.3%, respectively, with three additional A. maculatum (0.9%) coinfected. While R. parkeri-infected ticks were detected all three years (34.7% in 2013; 13.7% in 2014; 43.6% in 2015), "Ca. R. andeanae" was not detected in 2013, and was detected at rates of 10.8% in 2014, and 15.8% in 2015. Interestingly, rickettsial DNA levels in singly-infected ticks were significantly lower in "Ca. R. andeanae"-infected ticks compared to R. parkeri-infected ticks (P < 0.0001). Thus, both infection rates and rickettsial DNA levels were higher for R. parkeri than "Ca. R. andeanae." Infection rates of R. parkeri were also higher, and "Ca. R. andeanae" lower, here compared to A. maculatum reported previously in Kansas and Oklahoma. As we continue to monitor infection rates and levels, we anticipate that understanding temporal changes will improve our awareness of human risk for spotted fever rickettsioses. Further, these data may lead to additional studies to evaluate potential interactions among sympatric Rickettsia species in A. maculatum at the population level.
Assuntos
Vetores Aracnídeos/microbiologia , Ixodidae/microbiologia , Infecções por Rickettsia/transmissão , Rickettsia/isolamento & purificação , Animais , Vetores Aracnídeos/fisiologia , Humanos , Ixodidae/fisiologia , Mississippi , Rickettsia/genética , Rickettsia/fisiologia , Infecções por Rickettsia/microbiologiaRESUMO
The structure of chocolate is drastically transformed during oral processing from a composite solid to an oil/water fluid emulsion. Using two commercial dark chocolates varying in cocoa solids content, this study develops a method to identify the factors that govern lubrication in molten chocolate and saliva's contribution to lubrication following oral processing. In addition to chocolate and its individual components, simulated boluses (molten chocolate and phosphate buffered saline), in vitro boluses (molten chocolate and whole human saliva) and ex vivo boluses (chocolate expectorated after chewing till the point of swallow) were tested. The results reveal that the lubrication of molten chocolate is strongly influenced by the presence of solid sugar particles and cocoa solids. The entrainment of particles into the contact zone between the interacting surfaces reduces friction such that the maximum friction coefficient measured for chocolate boluses is much lower than those for single-phase Newtonian fluids. The addition of whole human saliva or a substitute aqueous phase (PBS) to molten chocolate dissolves sugar and decreases the viscosity of molten chocolate so that thinner films are achieved. However, saliva is more lubricating than PBS, which results in lower friction coefficients for chocolate-saliva mixtures when compared to chocolate-PBS mixtures. A comparison of ex vivo and in vitro boluses also suggests that the quantity of saliva added and uniformity of mixing during oral processing affect bolus structure, which leads to differences in measured friction. It is hypothesized that inhomogeneous mixing in the mouth introduces large air bubbles and regions of non-emulsified fat into the ex vivo boluses, which enhance wetting and lubrication.
Assuntos
Cacau/química , Cacau/metabolismo , Chocolate/análise , Boca/metabolismo , Fricção , Humanos , Lubrificação , ViscosidadeRESUMO
Several studies have suggested an association of mannose-binding lectin (MBL) deficiency with infections. In this study, we investigated the association between MBL deficiency and invasive fungal disease (IFD) in hematologic malignancy patients receiving myelosuppressive chemotherapy or hematopoietic stem cell transplant. MBL levels were quantified at the start of treatment in 152 patients who were followed for 6 months and scored as developing IFD or not. Forty-five patients (29.6%) developed IFD, of which 21 (46.7% of IFD cases and 13.8% of patients) were proven or probable IFD. Fifty-nine (38.8%) had MBL levels <1000 ng/mL. The rates of all IFD in patients with MBL levels below and above 1000 ng/mL were 33.9% and 26.9%, respectively (P=0.356). The rates of proven or probable IFD in patients with MBL levels below and above 1000 ng/mL were 11.9% and 15.1%, respectively (P=0.579). MBL levels <1000 ng/mL were not predictors of death (P=0.233). As expected, IFD was associated with death (P<0.0001). Our findings indicate that MBL levels <1000 ng/mL were not associated with an increased risk of developing IFD or overall survival.