Miracle-dz/UniFAR-FTUs huggingface dataset:
Protective ventilation for patients without acute respiratory distress syndrome.

To the Editor: Dr Serpa Neto and colleagues addressed the issue of whether the use of protective ventilation would be associated with a benefit in patients without acute respiratory distress syndrome (ARDS). However, this review was not without limitations, including the phenomenon in metaanalyses termed small study effects. Small study effects refer to the fact that small trials are more likely to report beneficial effects in the intervention group. In a meta-epidemiological study involving osteoarthritis trials, Nüesch et al found that small component trials reported a larger beneficial effect than larger trials, with a difference in effect size of 0.21. By restricting the metaanalysis to large trials, the significance of the beneficial effect disappeared. Such phenomena have been replicated in several other well-conducted meta-epidemiological studies. In the analysis by Serpa Neto et al, 17 of the 20 component trials enrolled fewer than 100 patients per group, which has been defined as a small trial by Nüesch et al. Of the remaining 3 large trials, 2 were nonrandomized, observational cohort studies. As a result, only 1 randomized controlled trial could be regarded as large. In Figure 2 of the article, the effect size of the large randomized trial was much smaller than the overall effect with respect to lung injury (risk ratio [RR], 0.67 [95% CI, 0.20-2.17] vs RR, 0.33 [95% CI, 0.23-0.47]). With respect to mortality, the large trial suggested that the protective ventilation strategy might be harmful (RR, 1.47 [95% CI, 0.15-14.38]). Furthermore, the cutoff point of 100 patients per group to distinguish between large and small studies is based on a continuous variable in the study by Nüesch et al. For binary outcomes as in the present study, the cutoff point may be even greater. While 100 patients per group guarantees at least 80% power to detect a 20% absolute risk difference between groups, it would still provide less than 80% power to detect a 50% relative risk reduction from a base mortality rate of 30% or 20%. In reality, a study of 200 patients may be too small to provide adequate power to detect plausible differences in mortality for most critical care interventions. Thus, conclusions drawn from the current meta-analysis can only be hypothesis-generating.
Newly delivered women's evaluation of personal health status and attitudes towards sickness absence and social benefits

Background. Unexpectedly high rates of sickness absence have been observed among pregnant women. No clear medical causes for illnesses reported as the basis for sick leave have yet been identified with certainty. An explanation proposed is the pregnant women's own attitudes towards their own states of well being during pregnancy. The aim of this study was to investigate the validity of this hypothesis.
Regulation of the Neutrophil Respiratory Burst Oxidase

Superoxide generation by the neutrophil respiratory burst oxidase (NADPH oxidase) can be reconstituted in a cell-free system using flavocytochrome b 558 and the cytosolic proteins p47 phox , p67 phox , and Rac. p47 phox functions as an adaptor protein; it increases the affinity of p67 phox and Rac in the NADPH oxidase complex, but is not essential when high concentrations of these proteins are used (Freeman, J. L., and Lambeth, J. D. (1996) J. Biol. Chem. 271, 22578–22582), implying that p67 phox and/or Rac directly regulates enzyme activity. Herein, we describe an activation domain in p67 phox that is essential for NADPH oxidase activity. A series of C-terminal truncation mutants of p67 phox showed that residues 211 to the C terminus (residue 526) are not needed for cell-free activity. However, shorter truncations were inactive, pointing to an activation domain within the region spanning residues 199–210. p67 phox mutated at single amino acid residues within this region showed diminished activity, and p67 phox V204A was completely inactive. The effects of mutations on activity were independent of p47 phox , and mutations did not affect the binding of p67 phox to Rac. In the presence of wild-type p67 phox , the V204A mutant was a potent inhibitor of superoxide generation, and inhibition was partially reversed by high concentrations of p67 phox , but not by p47 phox or Rac. The V204A mutant competed with native p67 phox for translocation to neutrophil plasma membrane, indicating that p67 phox V204A assembles to form an inactive complex. The data imply a direct activation of flavocytochrome b 558 by an activation domain in p67 phox .
A Fine-Grained, Uniform, Energy-Efficient Delay Element for FD-SOI Technologies

Contemporary digitally controlled delay elements trade off power overheads and delay quantization error. This paper proposes a new delay element that provides a balanced design that yields low power with low delay quantization error. The proposed element has a quasi linear delay characteristic, with uniform delay differences between adjacent code words. The element employs and leverages the advantages offered by a 28nm FD-SOI technology, using its back body biasing feature to add an extra dimension to its programmability. To do so, a novel generic delay shift block is proposed, which enables incorporating both fine and coarse delays in a single delay element that can be easily integrated into digital systems, an advantage over hybrid delay elements that rely on analog design.
Molecular cytogenetics of IGH rearrangements in non-Hodgkin B-cell lymphoma

Rearrangements involving the IGH gene have been identified in about 50% of non-Hodgkin B-cell lymphomas (NHLs) and correlated to clinically relevant subgroups. However, the detection rate largely varied with the technique used. We analyzed the incidence of IGH rearrangements using several fluorescence in situ hybridization (FISH) techniques on metaphases obtained from 96 patients with nodal NHL. An IGH rearrangement was identified in 71 cases (74%). A t(14;18)(q32;q21) was found in 37 of the 42 follicular lymphomas (88.1%) studied and a t(11;14)(q13;q32) in 12 of the 14 mantle cell lymphomas (85.7%). IGH rearrangements were identified in 21 of the 40 diffuse large B-cell lymphomas (52.5%), including seven t(14;18)(q32;q21) and four t(3;14)(q27;q32). Conventional cytogenetics was uninformative in several cases. However, the complemented analysis using 24-color FISH, chromosomal whole paints, telomeric probes and locus specific identifiers enabled us to characterize complex and/or masked IGH translocations in follicular lymphomas and mantle cell lymphomas and to identify all the chromosomal partners involved in IGH rearrangements in diffuse large B-cell lymphomas. This study shows the interest of using metaphase FISH in addition to conventional cytogenetics. Following banding techniques, FISH with the IGH dual color probe can be the first approach in NHL, after which chromosome painting and 24-color FISH can be used to identify the chromosomal partners involved in IGH rearrangements. The identification of these genes is of utmost importance for a better understanding of the molecular mechanisms involved in the genesis of lymphoma.
MRI-based hip cartilage measures in osteoarthritic and non-osteoarthritic individuals: a systematic review

Osteoarthritis is a common hip joint disease, involving loss of articular cartilage. The prevalence and prognosis of hip osteoarthritis have been difficult to determine, with various clinical and radiological methods used to derive epidemiological estimates exhibiting significant heterogeneity. MRI-based methods directly visualise hip joint cartilage, and offer potential to more reliably define presence and severity of osteoarthritis, but have been underused. We performed a systematic review of MRI-based estimates of hip articular cartilage in the general population and in patients with established osteoarthritis, using MEDLINE, EMBASE and SCOPUS current to June 2016, with search terms such as ‘hip’, ‘femoral head’, ‘cartilage’, ‘volume’, ‘thickness’, ‘MRI’, etc. Ultimately, 11 studies were found appropriate for inclusion, but they were heterogeneous in osteoarthritis assessment methodology and composition. Overall, the studies consistently demonstrate the reliability and potential clinical utility of MRI-based estimates. However, no longitudinal data or reference values for hip cartilage thickness or volume have been published, limiting the ability of MRI to define or risk-stratify hip osteoarthritis. MRI-based techniques are available to quantify articular cartilage signal, volume, thickness and defects, which could establish the sequence and rate of articular cartilage changes at the hip that yield symptomatic osteoarthritis. However, prevalence and rates of progression of hip osteoarthritis have not been established in any MRI studies in the general population. Future investigations could fill this important knowledge gap using robust MRI methods in population-based cross-sectional and longitudinal studies.
Asymptotic Mutual Information Statistics of Separately Correlated Rician Fading MIMO Channels

The asymptotic probability distribution of the mutual information of a separately correlated Rician fading multiple-input multiple-output (MIMO) channel is addressed. The mean and variance of the mutual information are derived when the number of transmit and receive antennas grows asymptotically large while their ratio approaches a finite constant. This derivation is based on the replica method, widely used in theoretical physics and, more recently, in the analysis of communication systems (code-division multiple access (CDMA) and MIMO). Though the replica method allows to analyze complex systems in a comparatively simple way, some authors pointed out that its assumptions are not always rigorous. It is shown that the mutual information converges asymptotically to a Gaussian distribution under mild technical conditions, which are tantamount to assuming that the spatial correlation structure has no asymptotically dominant eigenmodes. The accuracy of the asymptotic approach is assessed by numerical results. It is shown that the approximation is very accurate in a wide range of system settings, even when the number of transmit and receive antennas is as small as a few units.
Dramatic performance enhancements for the FASTER optimization algorithm

FASTER is a combinatorial optimization algorithm useful for finding low‐energy side‐chain configurations in side‐chain placement and protein design calculations. We present two simple enhancements to FASTER that together improve the computational efficiency of these calculations by as much as two orders of magnitude with no loss of accuracy. Our results highlight the importance of choosing appropriate initial configurations, and show that efficiency can be improved by stringently limiting the number of positions that are allowed to relax in response to a perturbation. The changes we describe improve the quality of solutions found for large‐scale designs, and allow them to be found in hours rather than days. The improved FASTER algorithm finds low‐energy solutions more efficiently than common optimization schemes based on the dead‐end elimination theorem and Monte Carlo. These advances have prompted investigations into new methods for force field parameterization and multiple state design. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1071–1075, 2006
Kinesin light chain-independent function of the Kinesin heavy chain in cytoplasmic streaming and posterior localisation in the Drosophila oocyte

Microtubules and the Kinesin heavy chain, the force-generating component of the plus end-directed microtubule motor Kinesin I are required for the localisation of oskar mRNA to the posterior pole of the Drosophila oocyte, an essential step in the determination of the anteroposterior axis. We show that the Kinesin heavy chain is also required for the posterior localisation of Dynein, and for all cytoplasmic movements within the oocyte. Furthermore, the KHC localises transiently to the posterior pole in an oskar mRNA-independent manner. Surprisingly, cytoplasmic streaming still occurs in kinesin light chain null mutants, and both oskar mRNA and Dynein localise to the posterior pole. Thus, the Kinesin heavy chain can function independently of the light chain in the oocyte, indicating that it associates with its cargoes by a novel mechanism.
Gamma Interferon Is Critical for Neuronal Viral Clearance and Protection in a Susceptible Mouse Strain following Early Intracranial Theiler's Murine Encephalomyelitis Virus Infection

ABSTRACT We evaluated the role of gamma interferon (IFN-γ) in protecting neurons from virus-induced injury following central nervous system infection. IFN-γ−/− and IFN-γ+/+ mice of the resistant major histocompatibility complex (MHC) H-2b haplotype and intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) cleared virus infection from anterior horn cell neurons. IFN-γ+/+H-2b mice also cleared virus from the spinal cord white matter, whereas IFN-γ−/−H-2b mice developed viral persistence in glial cells of the white matter and exhibited associated spinal cord demyelination. In contrast, infection of IFN-γ−/− mice of the susceptible H-2q haplotype resulted in frequent deaths and severe neurologic deficits within 16 days of infection compared to the results obtained for controls. Morphologic analysis demonstrated severe injury to spinal cord neurons in IFN-γ−/−H-2q mice during early infection. More virus RNA was detected in the brain and spinal cord of IFN-γ−/−H-2q mice than in those of control mice at 14 and 21 days after TMEV infection. Virus antigen was localized predominantly to anterior horn cells in infected IFN-γ−/−H-2q mice. IFN-γ deletion did not affect the humoral response directed against the virus. However, the level of expression of CD4, CD8, class I MHC, or class II MHC in the central nervous system of IFN-γ−/−H-2q mice was lower than those in IFN-γ+/+H-2q mice. Finally, in vitro analysis of virus-induced death in NSC34 cells and spinal motor neurons showed that IFN-γ exerted a neuroprotective effect in the absence of other aspects of the immune response. These data support the hypothesis that IFN-γ plays a critical role in protecting spinal cord neurons from persistent infection and death.
Clinical implications and prognostic role of minimal residual disease detection in follicular lymphoma

The identification of patients at high risk of relapse is a critical goal of modern translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is routinely employed in the management of patients with acute lymphoblastic leukemia. Current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders and particularly in follicular lymphoma (FL). Based on this evidence clinical trials employing MRD-based risk stratification are currently ongoing in FL. In this review the ‘state of the art’ of MRD evaluation in FL is discussed. A short description of technical issues and recent methodological advances is provided. Then, the bulk of the review focuses on critical take-home messages for clinicians working in the field. Finally, we discuss future perspectives of MRD detection and more generally outcome prediction in FL.
Flow cytometric identification of candidate normal stem cell populations in CD45‐negative B‐cell precursor acute lymphoblastic leukaemia

CD45‐negative B‐cell precursor acute lymphoblastic leukaemia (ALL) provides a unique model to study the stem cell compartment in ALL as leukaemic CD34‐positive cells, unlike their normal counterparts, do not express CD45. By increasing the number of events analysed to 106, storing only the events in the region of interest (storage gate), using appropriate isotype controls and stringent washing procedures, a flow cytometric protocol was established to characterize rare CD34+CD19− events. In eight of 12 patients (67%) with CD45‐negative B‐cell precursor ALL, a distinct CD34+CD19−CD45+ candidate normal stem cell population could be detected. In one patient analysed by four‐colour staining, the CD34+CD19−CD45+ cells, unlike the CD45‐negative leukaemic cells, expressed CD117 (c‐kit), providing further evidence that these cells represent residual non‐leukaemic normal cells. By multiparameter analysis, this population of candidate normal stem cells could be separated from contaminating leukaemic CD34+CD19−CD45−cells, which were detected in 11 of the 12 patients within the CD34+CD19− compartment.
High-quality chronic care delivery improves experiences of chronically ill patients receiving care

Objective Investigate whether high-quality chronic care delivery improved the experiences of patients. Design This study had a longitudinal design. Setting and Participants We surveyed professionals and patients in 17 disease management programs targeting patients with cardiovascular diseases, chronic obstructive pulmonary disease, heart failure, stroke, comorbidity and eating disorders. Main Outcome Measures Patients completed questionnaires including the Patient Assessment of Chronic Illness Care (PACIC) [T1 (2010), 2637/4576 (58%); T2 (2011), 2314/4330 (53%)]. Professionals' Assessment of Chronic Illness Care (ACIC) scores [T1, 150/274 (55%); T2, 225/325 (68%)] were used as a context variable for care delivery. We used two-tailed, paired t-tests to investigate improvements in chronic illness care quality and patients' experiences with chronic care delivery. We employed multilevel analyses to investigate the predictive role of chronic care delivery quality in improving patients' experiences with care delivery. Results Overall, care quality and patients' experiences with chronic illness care delivery significantly improved. PACIC scores improved significantly from 2.89 at T1 to 2.96 at T2 and ACIC-S scores improved significantly from 6.83 at T1 to 7.18 at T2. After adjusting for patients' experiences with care delivery at T1, age, educational level, marital status, gender and mental and physical quality of life, analyses showed that the quality of chronic care delivery at T1 (P < 0.001) and changes in care delivery quality (P < 0.001) predicted patients' experiences with chronic care delivery at T2. Conclusion This research showed that care quality and changes therein predict more positive experiences of patients with various chronic conditions over time.
American society for apheresis guidelines support use of red cell exchange transfusion for severe malaria with high parasitemia.

TO THE EDITOR—The American Society for Apheresis (ASFA) Special Issue Writing Committee read the article “Exchange transfusion for severe malaria: evidence base and literature review” by Tan et al with much interest [1]. The article concludes that exchange transfusion (ET) is not indicated in the setting of severe malaria. This recommendation contrasts with our evidence-based review, which supports ET as an adjunctive therapy [2]. Tan et al’s conclusion was based on analysis of cases of severe malaria reported to the US National Malaria Surveillance System from 1985 to 2010, supported by a literature review. They used a propensity score matching technique to select and compare 101 individuals with severe malaria who received ET with 314 who did not. The overall mortality rates of those receiving and not receiving ET were 17.8% and 15.9%, respectively, resulting in no statistically significant association between ET and survival outcomes; however, the study was underpowered to detect a difference in mortality of <10%. The expected difference in the mortality rate between no ET and ET to make it beneficial was set at 4.6% with 15.9% overall mortality. This implies that to consider ET as efficacious, one would need to see a 3-fold decrease in mortality (about 60%). We would like to highlight differences between these 2 publications, and indicate continued support of our conclusion. First, the vast majority of cases reviewed for the Special Issue had severe malaria and >10% parasitemia. By comparison, Tan et al studied cases of malaria infection plus at least cerebral malaria, renal failure, acute respiratory distress syndrome, severe anemia, parasitemia >5%, acidosis, hypotension, or disseminated intravascular coagulopathy. Their Table 1 reports that parasite density was unknown in >90% of cases [1]. Therefore, the assignment of malarial severity was predominantly based on clinical findings, rather than parasitemia. Given the importance of high parasitemia in the decision to perform ET, and in support of the therapeutic rationale of this modality, the effect of ET on mortality cannot be reliably judged in the absence of this pathobiological correlate. Next, there is a lack of important data, including the 38% of cases not having survival data (thus not being included in the study), and exclusion of 5 ET cases that resulted in survival. Last, the Special Issue uses literature published in English only, whereas Tan et al used literature published in multiple languages, utilizing an online translating service of potentially unproven accuracy [3].
CS369N: Beyond Worst-Case Analysis Lecture #2: Models of Data in Online Paging ∗

In last lecture’s notation, we have thus deﬁned cost(A,z) as the number of “page faults”(a.k.a. “cache misses”) that A incurs on the page request sequence z.We now come to astandard andimportant deﬁnition: the competitive ratio ofalgorithm Ais its worst-case performance relative to an optimal oﬄine algorithm OPT, which has full
Modulating the Structure of EGFR with UV Light: New Possibilities in Cancer Therapy

The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. EGFR is activated upon binding to e.g. epidermal growth factor (EGF), leading to cell survival, proliferation and migration. EGFR overactivation is associated with tumor progression. We have previously shown that low dose UVB illumination of cancer cells overexpressing EGFR prior to adding EGF halted the EGFR signaling pathway. We here show that UVB illumination of the extracellular domain of EGFR (sEGFR) induces protein conformational changes, disulphide bridge breakage and formation of tryptophan and tyrosine photoproducts such as dityrosine, N-formylkynurenine and kynurenine. Fluorescence spectroscopy, circular dichroism and thermal studies confirm the occurrence of conformational changes. An immunoassay has confirmed that UVB light induces structural changes in the EGF binding site. A monoclonal antibody which competes with EGF for binding sEGFR was used. We report clear evidence that UVB light induces structural changes in EGFR that impairs the correct binding of an EGFR specific antibody that competes with EGF for binding EGFR, confirming that the 3D structure of the EGFR binding domain suffered conformational changes upon UV illumination. The irradiance used is in the same order of magnitude as the integrated intensity in the solar UVB range. The new photonic technology disables a key receptor and is most likely applicable to the treatment of various types of cancer, alone or in combination with other therapies.