Category: Statistics

Sci Rep. 2021 Apr 16;11(1):8367. doi: 10.1038/s41598-021-87758-y.

ABSTRACT

The aim was to investigate the efficacy of prophylactic antibiotics for the prevention of febrile neutropenia (FN) during cabazitaxel therapy for castration-resistant prostate cancer (CRPC) with G-CSF. We retrospectively studied 443 cycles of cabazitaxel therapy given to 56 patients with CRPC at Keio University Hospital between May 2012 and August 2018. Statistical analysis was conducted to determine whether the combination of prophylactic G-CSF and antibiotics was more effective in preventing FN, compared with prophylactic G-CSF alone. Prophylactic PEG-G-CSF or G-CSF was administered in all 443 cycles. Only fluoroquinolones were used as prophylactic antibiotics and were administered in 328 cycles (74.0%). FN occurred in 5 cycles (1.1%). Prophylactic antibiotics were administered in 327 cycles (74.6%) in the FN-negative group and in only 1 cycle (20.0%) in the FN-positive group. Chi-square test indicated the incidence of FN was significantly lower in the group that received prophylactic antibiotics compared with the group that did not receive prophylactic antibiotics (P = 0.017). Compared with prophylactic G-CSF alone, prophylactic G-CSF and antibiotics significantly suppressed the occurrence of FN.

PMID:33863964 | DOI:10.1038/s41598-021-87758-y

Cell Death Discov. 2021 Apr 16;7(1):81. doi: 10.1038/s41420-021-00456-6.

ABSTRACT

Both tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.

PMID:33863878 | DOI:10.1038/s41420-021-00456-6

Nat Commun. 2021 Apr 16;12(1):2236. doi: 10.1038/s41467-021-21973-z.

ABSTRACT

Low-loss photonic integrated circuits and microresonators have enabled a wide range of applications, such as narrow-linewidth lasers and chip-scale frequency combs. To translate these into a widespread technology, attaining ultralow optical losses with established foundry manufacturing is critical. Recent advances in integrated Si₃N₄ photonics have shown that ultralow-loss, dispersion-engineered microresonators with quality factors Q > 10 × 10⁶ can be attained at die-level throughput. Yet, current fabrication techniques do not have sufficiently high yield and performance for existing and emerging applications, such as integrated travelling-wave parametric amplifiers that require meter-long photonic circuits. Here we demonstrate a fabrication technology that meets all requirements on wafer-level yield, performance and length scale. Photonic microresonators with a mean Q factor exceeding 30 × 10⁶, corresponding to 1.0 dB m^-1 optical loss, are obtained over full 4-inch wafers, as determined from a statistical analysis of tens of thousands of optical resonances, and confirmed via cavity ringdown with 19 ns photon storage time. The process operates over large areas with high yield, enabling 1-meter-long spiral waveguides with 2.4 dB m^-1 loss in dies of only 5 × 5 mm² size. Using a response measurement self-calibrated via the Kerr nonlinearity, we reveal that the intrinsic absorption-limited Q factor of our Si₃N₄ microresonators can exceed 2 × 10⁸. This absorption loss is sufficiently low such that the Kerr nonlinearity dominates the microresonator’s response even in the audio frequency band. Transferring this Si₃N₄ technology to commercial foundries can significantly improve the performance and capabilities of integrated photonics.

PMID:33863901 | DOI:10.1038/s41467-021-21973-z

Sci Rep. 2021 Apr 16;11(1):8358. doi: 10.1038/s41598-021-87113-1.

ABSTRACT

Climate seems to influence the spread of SARS-CoV-2, but the findings of the studies performed so far are conflicting. To overcome these issues, we performed a global scale study considering 134,871 virologic-climatic-demographic data (209 countries, first 16 weeks of the pandemic). To analyze the relation among COVID-19, population density, and climate, a theoretical path diagram was hypothesized and tested using structural equation modeling (SEM), a powerful statistical technique for the evaluation of causal assumptions. The results of the analysis showed that both climate and population density significantly influence the spread of COVID-19 (p < 0.001 and p < 0.01, respectively). Overall, climate outweighs population density (path coefficients: climate vs. incidence = 0.18, climate vs. prevalence = 0.11, population density vs. incidence = 0.04, population density vs. prevalence = 0.05). Among the climatic factors, irradiation plays the most relevant role, with a factor-loading of – 0.77, followed by temperature (- 0.56), humidity (0.52), precipitation (0.44), and pressure (0.073); for all p < 0.001. In conclusion, this study demonstrates that climatic factors significantly influence the spread of SARS-CoV-2. However, demographic factors, together with other determinants, can affect the transmission, and their influence may overcome the protective effect of climate, where favourable.

PMID:33863938 | DOI:10.1038/s41598-021-87113-1

Pediatrics. 2021 Apr 16:e20201500. doi: 10.1542/peds.2020-1500. Online ahead of print.

ABSTRACT

BACKGROUND: In preterm infants who require mechanical ventilation (MV), volume-targeted ventilation (VTV) modes are associated with lower rates of bronchopulmonary dysplasia compared with pressure-limited ventilation. Bronchopulmonary dysplasia rates in our NICU were higher than desired, prompting quality improvement initiatives to improve MV by increasing the use of VTV.

METHODS: We implemented and tested interventions over a 3-year period. Primary outcomes were the percentage of conventional MV hours when any-VTV mode was used and the percentage of conventional MV hours when an exclusively VTV mode was used. Exclusively VTV modes were modes in which all breaths were volume targeted. We evaluated outcomes during 3 project periods: baseline (May 2016-December 2016); epoch 1 (December 2016-October 2018), increasing the use of any-VTV mode; and epoch 2 (October 2018-November 2019), increasing the use of exclusively VTV modes.

RESULTS: Use of any-VTV mode increased from 18 694 of 22 387 (83%) MV hours during baseline to 72 846 of 77 264 (94%) and 58 174 of 60 605 (96%) MV hours during epochs 1 and 2, respectively (P < .001). Use of exclusively VTV increased from 5967 of 22 387 (27%) during baseline to 47 364 of 77 264 (61%) and 46 091 of 60 605 (76%) of all conventional MV hours during epochs 1 and 2, respectively (P < .001). In statistical process control analyses, multiple interventions were associated with improvements in primary outcomes. Measured clinical outcomes were unchanged.

CONCLUSIONS: Quality improvement interventions were associated with improved use of VTV but no change in measured clinical outcomes.

PMID:33863843 | DOI:10.1542/peds.2020-1500

Pain. 2021 Apr 8. doi: 10.1097/j.pain.0000000000002287. Online ahead of print.

ABSTRACT

Because chronic chronic pain has been poorly represented in the International statistical classification of diseases and related health problems (ICD) despite its significant contribution to the burden of disease worldwide, the International Association for the Study of Pain (IASP) developed a classification of chronic pain that was included in the ICD-11 version as ‘MG30’ and approved by the World Health Assembly in 2019. The objective of this field test was to determine its properties. A web-based survey using the WHO-FiT platform recruited 177 health-care professionals from all WHO regions. Following a training on coding chronic pain hosted by the IASP website, participants evaluated 18 diagnostic codes (lines) of the 2017 frozen version of the ICD-11 and 12 vignettes (cases) describing chronic pain conditions. Correctness, ambiguity and perceived difficulty of the coding were compared between the ICD-11 and the ICD-10 and the applicability of the morbidity rules for the ICD-11 verified. In the line coding, 43.0% of correct chronic pain diagnoses assigned with the ICD-10 contrasted with 63.2% with the ICD-11. Especially in cases in which the chronic pain is regarded as the symptom of an underlying disease, the ICD-11 (63.5%) commanded more correct diagnoses than the ICD-10 (26.8%). The case coding was on average 83.9% accurate, only in 1.6% of cases any difficulty was perceived. The morbidity rules were applied correctly in 74.1% of cases. From a coding perspective, the ICD-11 is superior to the ICD-10 in every respect, offering better accuracy, difficulty and ambiguity in coding chronic pain conditions.

PMID:33863861 | DOI:10.1097/j.pain.0000000000002287

Pain. 2021 Apr 7. doi: 10.1097/j.pain.0000000000002298. Online ahead of print.

ABSTRACT

The net effects of prescribing initiatives that encourage dose reductions are uncertain. We examined whether rapid dose reduction after high dose chronic opioid treatment (COT) associates with suicide, overdose, or other opioid-related adverse events. This retrospective cohort study included Oregon Medicaid recipients with high-dose COT. Claims were linked with prescription data from the Prescription Drug Monitoring Program (PDMP) and death data from vital statistics, 2014 to 2017. Participants were placed into four mutually exclusive dose trajectory groups following the high-dose COT period, and Cox proportional hazard models were used to examine the effect of dose changes on patient outcomes in the following year. Of the 14,596 high-dose COT patients, 4,191 (28.7%) abruptly discontinued opioid prescriptions, 1,648 (11.3%) reduced opioid dose prior to discontinuing, 6,480 (44.4%) had a dose reduction but never discontinued, and 2,277 (15.6%) had a stable or increasing dose. Discontinuation, whether abrupt (adjusted hazard ratio (aHR) 3.63; 95% CI 1.42-9.25) or with dose reduction (aHR 4.47, 95% CI 1.68-11.88) significantly increased risk of suicide compared to those with stable or increasing dose. In contrast, discontinuation or dose reduction reduced the risk of overdose compared to those with a stable or increasing dose (aHR 0.36 – 0.62, 95% CI 0.20 – 0.94). Patients with an abrupt discontinuation were more likely to overdose on heroin (vs. prescription opioids) than patients in other groups (p<0.0001). Our study suggests that patients on COT require careful risk assessment and supportive interventions when considering opioid discontinuation or continuation at a high dose.

PMID:33863865 | DOI:10.1097/j.pain.0000000000002298

Genome Res. 2021 Apr 16. doi: 10.1101/gr.270033.120. Online ahead of print.

ABSTRACT

The members of the tribe Brassiceae share a whole-genome triplication (WGT), and one proposed model for its formation is a two-step pair of hybridizations producing hexaploid descendants. However, evidence for this model is incomplete, and the evolutionary and functional constraints that drove evolution after the hexaploidy are even less understood. Here, we report a new genome sequence of Crambe hispanica, a species sister to most sequenced Brassiceae. Using this new genome and three others that share the hexaploidy, we traced the history of gene loss after the WGT using the Polyploidy Orthology Inference Tool (POInT). We confirm the two-step formation model and infer that there was a significant temporal gap between those two allopolyploidizations, with about a third of the gene losses from the first two subgenomes occurring before the arrival of the third. We also, for the 90,000 individual genes in our study, make parental subgenome assignments, inferring, with measured uncertainty, from which of the progenitor genomes of the allohexaploidy each gene derives. We further show that each subgenome has a statistically distinguishable rate of homoeolog losses. There is little indication of functional distinction between the three subgenomes: the individual subgenomes show no patterns of functional enrichment, no excess of shared protein-protein or metabolic interactions between their members, and no biases in their likelihood of having experienced a recent selective sweep. We propose a “mix and match” model of allopolyploidy, in which subgenome origin drives homoeolog loss propensities but where genes from different subgenomes function together without difficulty.

PMID:33863805 | DOI:10.1101/gr.270033.120

Genome Res. 2021 Apr 16. doi: 10.1101/gr.266049.120. Online ahead of print.

ABSTRACT

Extreme phenotypic diversity, a history of artificial selection, and socioeconomic value make domestic dog breeds a compelling subject for genomic research. Copy number variation (CNV) is known to account for a significant part of inter-individual genomic diversity in other systems. However, a comprehensive genome-wide study of structural variation as it relates to breed-specific phenotypes is lacking. We have generated whole genome CNV maps for more than 300 canids. Our data set extends the canine structural variation landscape to more than 100 dog breeds, including novel variants that cannot be assessed using microarray technologies. We have taken advantage of this data set to perform the first CNV-based genome-wide association study (GWAS) in canids. We identify 96 loci that display copy number differences across breeds, which are statistically associated with a previously compiled set of breed-specific morphometrics and disease susceptibilities. Among these, we highlight the discovery of a long-range interaction involving a CNV near MED13L and TBX3, which could influence breed standard height. Integration of the CNVs with chromatin interactions, long noncoding RNA expression, and single nucleotide variation highlights a subset of specific loci and genes with potential functional relevance and the prospect to explain trait variation between dog breeds.

PMID:33863806 | DOI:10.1101/gr.266049.120

Eur Respir J. 2021 Apr 16:2004656. doi: 10.1183/13993003.04656-2020. Online ahead of print.

ABSTRACT

RATIONALE: Patients with concomitant features of asthma and chronic obstructive pulmonary disease (COPD) have a heavy disease burden.

OBJECTIVES: Using data collected prospectively in the European Community Respiratory Health Survey, we compared the risk factors, clinical history, and lung function trajectories from early adulthood to the late sixties of middle aged subjects having asthma+COPD (n=179), past (n=263) or current (n=808) asthma alone, COPD alone (n=111), or none of these (n=3477).

METHODS: Interview data and prebronchodilator FEV₁ and FVC were obtained during three clinical examinations in 1991-1993, 1999-2002, and 2010-2013. Disease status was classified in 2010-2013, when the subjects were aged 40-68, according to the presence of fixed airflow obstruction (postbronchodilator FEV₁/FVC below the lower limit of normal), a lifetime history of asthma, and cumulative exposure to tobacco or occupational inhalants. Previous lung function trajectories, clinical characteristics, and risk factors of these phenotypes were estimated.

MAIN RESULTS: Subjects with asthma+COPD reported maternal smoking (28.2%) and respiratory infections in childhood (19.1%) more frequently than subjects with COPD alone (20.9 and 14.0%, respectively). Subjects with asthma+COPD had an impairment of lung function at age 20 that tracked over adulthood, and more than half of them had asthma onset in childhood. Subjects with COPD alone had the highest lifelong exposure to tobacco smoking and occupational inhalants, and they showed accelerated lung function decline during adult life.

CONCLUSIONS: The coexistence between asthma and COPD seems to have its origins earlier in life compared to COPD alone. These findings suggest that prevention of this severe condition, which is typical at older ages, should start in childhood.

PMID:33863744 | DOI:10.1183/13993003.04656-2020