In this study we examine the impact of the strength of the large-scale motions on the amplitude and frequency of the small scales in high-Reynolds-number turbulent boundary layers. Time series of ...hot-wire data are decomposed into large- and small-scale components, and the impact of the large scale on the amplitude and frequency of the small scales is considered. The amplitude modulation effect is examined by conditionally averaging the small-scale intensity (
${ u}_{S}^{2} $
) for various values of the large-scale fluctuation (
${u}_{L} $
). It is shown that
${ u}_{S}^{2} $
increases with increasing value of
${u}_{L} $
in the near-wall region, whereas, farther away from the wall,
${ u}_{S}^{2} $
decreases with increasing
${u}_{L} $
. The rate of increase in small-scale intensity with the strength of the large-scale signal is neither symmetric (about
${u}_{L} = 0$
) nor linear. The extent of the frequency modulation is examined by counting the number of occurrences of local maxima or minima in the small-scale signal. It is shown that the frequency modulation effect is confined to the near-wall region and its extent diminishes rapidly beyond
${y}^{+ } = 100$
. A phase lag between the large- and small-scale fluctuations, in terms of amplitude modulation, has also been identified, which is in agreement with previous studies. The phase lag between large- and small-scale fluctuations for frequency modulation is comparable to that of amplitude modulation in the near-wall region. The combined effect of both amplitude and frequency modulation is also examined by computing conditional spectra of the small-scale signal conditioned on the large scales. In the near-wall region, the results indicate that the peak value of pre-multiplied spectra increases with increasing value of
${u}_{L} $
, indicating amplitude modulation, while the frequency at which this peak occurs also increases with increasing value of
${u}_{L} $
, revealing frequency modulation. The overall trends observed from the conditional spectra are consistent with the results obtained through statistical analyses. Finally, a physical mechanism that can capture most of the above observations is also presented.
Background
Laparoscopic liver resection has been increasingly adopted worldwide as a result of the rapid advancement in surgical techniques and equipment. This study aims to determine the factors ...associated with and outcomes of open conversion after laparoscopic minor hepatectomy (LMH) based on a single center multi-surgeon experience.
Methods
This is a retrospective review of the first 147 consecutive LMH performed between 2006 and April 2014 at a single institution. Data on patient demographics, pathology results, perioperative outcomes, and operative results were collected. Factors associated with open conversion were analyzed via univariate analysis and a
P
value <.05 was considered statistically significant.
Results
LMH was performed for malignancy in 114 (77.6 %) patients of which hepatocellular carcinoma (
n
= 82) and colorectal metastases (
n
= 16) were the most common pathologies. Forty-one (27.9 %) patients had cirrhotic livers and 18 (15.7 %) had fibrotic livers. Fifty patients (44 %) had concomitant surgery in addition to LMH. Twenty (13.6 %) procedures required open conversion and the most common reason was for bleeding (
n
= 12). Twenty-five patients (17 %) experienced postoperative complications. Univariate analyses demonstrated that only individual surgeon volume (
n
≤ 10 cases) 15 (24.2 %) vs 5 (5.9 %),
P
= .001 and institution volume (
n
≤ 25 cases) 8 (32 %) vs 12 (9.8 %),
P
= .003 were factors associated with open conversion. Open conversion was significantly associated with increased intra-operative blood loss, increased intra-operative blood transfusion, increased postoperative morbidity, and longer postoperative stay.
Conclusions
Individual surgeon and institution volumes were important factors associated with open conversion after LMH. Open conversion after LMH resulted in poorer outcomes compared to procedures that were successfully completed laparoscopically.
Background
Most studies analyzing the learning experience of laparoscopic liver resection (LLR) focused on the experience of one or two expert pioneering surgeons. This study aims to critically ...analyze the impact of individual surgeon experience on the outcomes of LLR based on the contemporary collective experiences of multiple surgeons at single institution.
Methods
Retrospective review of 324 consecutive LLR from 2006 to 2016. The cases were performed by 10 surgeons over various time periods. Four surgeons had individual experience with <20 cases, four surgeons with 20–30 cases, and two surgeons with >90 cases. The cohort was divided into two groups: comparing a surgeon’s experience between the first 20, 30, 40, and 50 cases with patients treated thereafter. Similarly, we performed subset analyses for anterolateral lesions, posterosuperior lesions, and major hepatectomies.
Results
As individual surgeons gained increasing experience, this was significantly associated with older patients being operated, decreased hand-assistance, larger tumor size, increased liver resections, increased major resections, and increased resections of tumors located at the posterosuperior segments. This resulted in significantly longer operation time and increased use of Pringle maneuver but no difference in other outcomes. Analysis of LLR for tumors in the posterosuperior segments demonstrated that there was a significant decrease in conversion rates after a surgeon had experience with 20 LLR. For major hepatectomies, there was a significant decrease in morbidity, mortality, and length of stay after acquiring experience with 20 LLR.
Conclusion
LLR can be safely adopted today especially for lesions in the anterolateral segments. LLR for lesions in the difficult posterosuperior segments and major hepatectomies especially in cirrhosis should only be attempted by surgeons who have acquired a minimum experience with 20 LLR.
The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs).
To assess the association of qSOFA with excess ...hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria.
Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas.
Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 best to 3 worst) or SIRS criteria (range, 0 best to 4 worst) within 24 hours of presentation to study hospital.
Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary).
The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% 95% CI, 11%-14%; odds ratio, 3.6 95% CI, 3.0-4.2) and across cohorts (P < .05 for 8 of 9 cohorts). Compared with a low qSOFA score, a moderate qSOFA score was also associated with increased risk of death overall (8% vs 3%; difference, 5% 95% CI, 4%-6%; odds ratio, 2.8 95% CI, 2.0-3.9), but not in every cohort (P < .05 in 2 of 7 cohorts). High, vs low or moderate, SIRS criteria were associated with a smaller increase in risk of death overall (13% vs 8%; difference, 5% 95% CI, 3%-6%; odds ratio, 1.7 95% CI, 1.4-2.0) and across cohorts (P < .05 for 4 of 9 cohorts). qSOFA discrimination (area under the receiver operating characteristic curve AUROC, 0.70 95% CI, 0.68-0.72) was superior to that of both the baseline model (AUROC, 0.56 95% CI, 0.53-0.58; P < .001) and SIRS (AUROC, 0.59 95% CI, 0.57-0.62; P < .001).
When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.
Background
Historically, the benefit of liver resection for non-colorectal, non-neuroendocrine (NCNN) liver metastases has been controversial. This study aims to determine the preoperative prognostic ...factors of liver resection for NCNN liver metastases and validate the Adam score in an Asian population.
Methods
Consecutive patients who underwent liver resection for NCNN liver metastases were identified retrospectively from a prospective liver resection database of the single institution between 2001 and 2014. Univariate Cox regression models were used to identify associations with outcome variables. Recurrence-free interval and overall survival were determined using the Kaplan–Meier method and compared using log-rank test.
Results
Seventy-eight consecutive patients were identified, which met the study criteria. Univariate analysis demonstrated that adenocarcinoma histology of primary cancer, disease-free interval and number of nodules were significant predictors of survival. Four of the six components of Adam score were significant predictors of survival. These were the presence of extrahepatic metastases, R2 resection, disease-free interval and type of a primary tumour. The total Adam score was also a significant predictor of survival.
Conclusion
Liver resection for NCNN liver metastases is a safe and viable treatment option in carefully selected patients. Significant preoperative prognostic factors include adenocarcinoma primary tumours, disease-free interval and number of nodules. The total Adam score was a good predictor of overall survival and can be used to risk stratify patients undergoing hepatic resection for NCNN liver metastases.
Wall-bounded turbulence, where it occurs in engineering or nature, is commonly subjected to spatial variations in wall shear stress. A prime example is spatially varying roughness. Here, we ...investigate the configuration where the wall shear stress varies only in the lateral direction. The investigation is idealised in order to focus on one aspect, namely, the similarity and structure of turbulent inertial motion over an imposed scale of stress variation. To this end, we analyse data from direct numerical simulation (DNS) of pressure-driven turbulent flow through a channel bounded by walls of laterally alternating patches of high and low wall shear stress. The wall shear stress is imposed as a Neumann boundary condition such that the wall shear stress ratio is fixed at 3 while the lateral spacing
$s$
of the uniform-stress patches is varied from 0.39 to 6.28 of the half-channel height
$\unicodeSTIX{x1D6FF}$
. We find that global outer-layer similarity is maintained when
$s$
is less than approximately
$0.39\unicodeSTIX{x1D6FF}$
while local outer-layer similarity is recovered when
$s$
is greater than approximately
$6.28\unicodeSTIX{x1D6FF}$
. However, the transition between the two regimes through
$s\approx \unicodeSTIX{x1D6FF}$
is not monotonic owing to the presence of secondary roll motions that extend across the whole cross-section of the flow. Importantly, these secondary roll motions are associated with an amplified skin-friction coefficient relative to both the small- and large-
$s/\unicodeSTIX{x1D6FF}$
limits. It is found that the relationship between the secondary roll motions and the mean isovels is reversed through this transition from low longitudinal velocity over low stress at small
$s/\unicodeSTIX{x1D6FF}$
to high longitudinal velocity over low stress at large
$s/\unicodeSTIX{x1D6FF}$
.
MicroRNA-224 (miR-224) is frequently over-expressed in liver and colorectal cancers. We and others have previously described the role of miR-224 over-expression in cell proliferation in vitro but we ...have yet to identify the relevant miR-224 direct target. In this study, we further demonstrated that miR-224 up-regulation promotes cell proliferation using both in vitro assays and in vivo tumor growth models. We systematically screened for high confidence miR-224 targets by overlapping in silico predicted targets from multiple algorithms and significantly down-regulated genes in miR-224-expressing cells from whole genome expression microarrays. A total of 72 high confidence miR-224 targets were identified and found to be enriched in various cancer-related processes. SMAD family member 4 (SMAD4) is experimentally validated as the direct cellular target through which miR-224 promotes cell proliferation. The clinical relevance of our experimental observations was supported by a statistically significant inverse correlation between miR-224 and SMAD4 transcript expression in tumor versus paired adjacent non-tumorous tissues from HCC patients (p<0.001, r= -0.45, R(2) =0.122). Furthermore, miR-224 up-regulation and SMAD4 down-regulation is significantly associated with poorer patient survival (p<0.05). In summary, miR-224/SMAD4 pathway is a clinically relevant pathway to provide new insights in understanding HCC. (191 words).
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion ...partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.