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Purpose The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions. Methods We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). Results Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P

BackgroundTo date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19.MethodsWe included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until intensive care unit (ICU) death or discharge. We examined factors and trajectories that determined disease progression and responsiveness to interventions used in acute respiratory distress syndrome (ARDS). Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU).FindingsData for 633 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median PaO2/FiO2 in non-survivors on the day of death was 12.3(8.9-18.4) kPa suggesting severe refractory hypoxaemia as a major contributor to mortality. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (60.4% versus 17.6%; PInterpretationA sizeable proportion of patients with progressive worsening of hypoxaemia had no application of and were refractory to evidence based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID-19 patients refractory to conventional management strategies will be critical to improving future outcomes.Research in contextEvidence before this studyBeyond the regular literature expertise of our consortium, we enhanced our literature review - due to the fast-evolving Covid-19 publication situation-by searching PubMed for articles published in English or with English language abstracts on October 26, 2020 (and before), with the terms “mechanical ventilation”, “prone position”, “AND (“coronavirus” OR “COVID-19”). Studies including patients not receiving ventilation were excluded, as were those reporting on paediatric and single-centre populations. Note, that neither of those studies analysed the data with respect to the temporal evolution of patients and at our level of granularity. Only four multicentre studies reported detailed ventilator settings and outcomes in ventilated patients with COVID-19. All studies showed only ventilator settings with restricted time points either on admission or the first 4 days of admission. None enabled granular visualisation and analysis of longitudinal ICU trajectory and management.Added value of this studyThis study provides a comprehensive analysis and visualisation of routine clinical measurements tracking the whole ICU time course of patients undergoing invasive mechanical ventilation for COVID-19. Mechanically ventilated patients with COVID-19 have a different natural history and trajectory from descriptions of non-COVID ARDS patients, not predictable from admission physiology. Refractory hypoxaemia is an attributable factor associated with poor outcomes in Covid-19 and hence, understanding of use and utility of evidence-based ARDS interventions is clinically crucial. Opportunities to apply prone positioning appropriately are frequently missed, application of high levels of PEEP, and higher tidal volume delivery than planned is common. Lack of responsiveness to advanced ARDS management is associated with hypercoagulation and cardiovascular instability. These data may help homogenise future clinical management protocols and suggest change-of-practice trials.Implications of all the available evidenceThis study shows that disease progression in Covid-19 during the first surge occurred more frequently and for longer than other forms of respiratory failure from pre-Covid19 studies. Furthermore, variations in clinical practise occur across sites which may benefit from standardisation of evidence-based practise. Patients that do not resolve hypoxaemia over the first week have a significantly higher mortality, and, crucially, that a significant proportion are refractory to prone interventions and show variability in responses to PEEP changes. Opportunities to implement prone position were missed in many patients and this was compounded with its reduced effect on oxygenation with delayed application. This lack of responsiveness is related to indices of inflammation, thrombosis, and cardiac dysfunction suggesting that pulmonary thrombosis could influence prone responsiveness and should be pro-actively investigated in the setting of refractory Covid-19 ARDS. Prediction of failure to resolve or respond to ARDS interventions could further focus research on this group with worse outcome.

Burkholderia pseudomallei is the causative agent of melioidosis. While adaptive immunity has been shown to be important for host resistance to B. pseudomallei , the direct interaction of the bacteria with adaptive immune cells such as T and B cells is not well known. To address this question, we infected Jurkat T cells, as well as human primary CD4 + and CD8 + T cells, with live B. pseudomallei . We found that live bacterial infection could costimulate T cells to produce interleukin-2 (IL-2) and gamma interferon (IFN-γ) in the presence of anti-CD3 cross-linking antibodies. Bacterial supernatant could also costimulate T cells, and this was due to the presence of flagellin in the supernatant. However, T cells infected with bacterial mutants lacking flagellin showed strong impairment in IL-2 but only a slight impairment in IFN-γ production. When cross-linking of CD3 is replaced by IL-2, live bacterial infection was still able to costimulate human primary T cells to produce IFN-γ and flagellin is only a minor ligand contributing to this costimulation. Thus, live B. pseudomallei could potentially costimulate T cells not only in an antigen-specific manner but also in a nonspecific manner through bystander activation via IL-2.

Humic acid (HA) in well water used by the inhabitants for drinking is one of the possible etiological factors for blackfoot disease (BFD). Moreover, within BFD endemic areas cancers occur at significantly higher rates than in areas free of BFD. In this study, the genotoxic potential of HA is assessed using human peripheral blood lymphocytes. The cells were exposed to HA (0–200 μg/mL for 2 h), and the induction of DNA primary damage in cellular DNA was evaluated by single-cell gel electrophoresis (comet assay). HA-induced DNA damage was decreased by superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), and reactive oxygen species (ROS) scavengers (superoxide dismutase, catalase, and Trolox), and nitric oxide (NO) synthase inhibitors ( N G -nitro- l -arginine methyl ester and N G -methyl- l -arginine). Moreover, formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Endo III), known to catalyze the excision of oxidized bases, increase the amount of DNA migration in HA-treated cells. Pretreatment of the cells with both the Ca 2+ -chelator BAPTA and EGTA completely inhibited HA-induced DNA damage, indicating that HA-induced changes in Ca 2+ -homeostasis are the predominant pathways for the HA induction of genotoxicity. Furthermore, sister chromatid exchange was found in the HA-treated lymphocytes. Our findings suggest that HA can induce oxidative DNA damage and genotoxicity in human lymphocytes.

Preterm delivery (PTD) is the leading cause of infant morbidity and mortality in the United States. An epidemiological association between PTD and various bacteria that are part of the vaginal microflora has been reported. No single bacterial species has been identified as being causally associated with PTD, suggesting a multifactorial etiology. Quantitative microbiologic cultures have been used previously to define normal vaginal microflora in a predictive model. These techniques have been applied to vaginal swab cultures from pregnant women in an effort to develop predictive microbiologic models for PTD. Logistic regression analysis with microbiologic information was performed for various risk groups, and the probability of a PTD was calculated for each subject. Four predictive models were generated by using the quantitative microbiologic data. The area under the curve (AUC) for the receiver operating curves ranged from 0.74 to 0.94, with confidence intervals (CI) ranging from 0.62 to 1. The model for the previous PTD risk group with the highest percentage of PTDs had an AUC of 0.91 (CI, 0.79 to 1). It may be possible to predict PTD by using microbiologic risk factors measured once the gestation period has reached the 20-week time point.

The epidemiology of early onset neonatal group B streptococcal (GBS) disease has changed appreciably, but there are no recent assessments of the in-hospital resource utilization it incurs.We performed a retrospective cohort study of infants delivered from 1987 through 1995 at Massachusetts' largest obstetrics hospital. A matched cohort design was used to assess care occurring after transfer to another acute care hospital.There were 135 cases of early onset neonatal GBS infection complicating 85,062 deliveries (1.6/1,000 births) in 9 years, with a substantial decline beginning in 1994, when maternal intrapartum chemoprophylaxis was widely introduced. Most (73%) infants had birth weights of 2500 g or more; 93% survived. Overall both the median and mean lengths of stay were 8 days longer for infants with GBS disease than for those without this infection (P0.001). Total hospital charges for neonates with GBS disease also were higher, with the difference in medians of $5323 and in means of $10,004 (P0.001). Differences were greatest among2500-g birth weight infants; no excess was evident for infants with birth weights of1500 g.There was a substantial excess length of stay and charges associated with early onset neonatal GBS disease, although this was less than previously reported.

This study investigated the similarities and differences in perception of Cantonese tones and English stress patterns by Cantonese-English bilingual children, adults, and English monolingual adults. All three groups were asked to discriminate pairs of syllables that minimally differed in either Cantonese tone or in English stress. Bilingual children's performance on tone perception was comparable to their performance on stress perception. By contrast, bilingual adults' performance on tone perception was lower than their performance on stress perception, and there was a similar pattern in English monolingual adults. Bilingual adults tended to perform better than English monolingual adults on both the tone and stress perception tests. A significant correlation between tone perception and stress perception performance was found in bilingual children but not in bilingual adults. All three groups showed lower accuracy in the high rising-low rising contrast than any of the other 14 Cantonese tone contrasts. The acoustic analyses revealed that average F0, F0 onset, and F0 major slope were the critical acoustic correlates of Cantonese tones, whereas multiple acoustic correlates were salient in English stress, including average F0, spectral balance, duration and intensity. We argue that participants' difficulty in perceiving high rising-low rising contrasts originated from the contrasts' similarities in F0 onset and average F0; indeed the difference between their major slopes was the only cue with which to distinguish them. Acoustic-perceptual correlation analyses showed that although the average F0 and F0 onset were associated with tone perception performance in all three groups, F0 major slope was only associated with tone perception in the bilingual adult group. These results support a dynamic interactive account of suprasegmental speech perception by emphasizing the positive prosodic transfer between Cantonese tone and English stress, and the role that level of bilingual language experience and age play in shaping suprasegmental speech perception.

To investigate the intensity-modulated radiotherapy (IMRT) strategy in dose escalation of prostate and pelvic lymph nodes.Plan dosimetric data of 10 prostate cancer patients were compared with two-dimensional (2D) or IMRT techniques for pelvis (two-dimensional whole pelvic radiation therapy [2D-WPRT] or IM-WPRT) to receive 50 Gy or 54 Gy and additional prostate boost by three-dimensional conformal radiation therapy or IMRT (3D-PBRT or IM-PBRT) techniques up to 72 Gy or 78 Gy. Dose-volume histograms (DVHs), normal tissue complication probabilities (NTCP) of critical organ, and conformity of target volume in various combinations were calculated.In DVH analysis, the plans with IM-WPRT (54 Gy) and additional boost up to 78 Gy had lower rectal and bladder volume percentage at 50 Gy and 60 Gy, compared with those with 2D-WPRT (50 Gy) and additional boost up to 72 Gy or 78 Gy. Those with IM-WPRT (54 Gy) also had better small bowel sparing at 30 Gy and 50 Gy, compared with those with 2D-WPRT (50 Gy). In NTCP, those with IM-WPRT and total dose of 78 Gy achieved lower complication rates in rectum and small bowel, compared with those of 2D-WPRT with total dose of 72 Gy. In conformity, those with IM-WPRT had better conformity compared with those with 2D-WPRT with significance (p0.005). No significant difference in DVHs, NTCP, or conformity was found between IM-PBRT and 3D-PBRT after IM-WPRT.Initial pelvic IMRT is the most important strategy in dose escalation and critical organ sparing. IM-WPRT is recommended for patients requiring WPRT. There is not much benefit for critical organ sparing by IMRT after 2D-WPRT.

Bidens pilosa (B. pilosa) is well known in Taiwan as a traditional Chinese medicine. The purpose of this study was to evaluate the ability of both the ethanol (EtOH) and ethylacetate/ethanol (EA/EtOH) extracts from the whole B. pilosa plant, to protect normal human erythrocytes against oxidative damage in vitro. It was determined that the oxidative hemolysis and lipid/protein peroxidation of erythrocytes induced by the aqueous peroxyl radical [2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)] were suppressed by both EtOH (50–150 μg/ml) and EA/EtOH (25–75 μg/ml) extracts of B. pilosa in concentration- and time-dependent manners. B. pilosa extracts also prevented the decline of superoxide dismutase (SOD) activity and the depletion of cytosolic glutathione (GSH) and ATP in erythrocytes. These results imply that B. pilosa may have protective antioxidant properties.

The design of a pilot study to assess the feasibility of conducting a full-scale trial of blind refereeing for the Institute of Mathematical Satistics's journals is proposed. Issues related to the choice of outcome measure, methods of randomization, number of reviewers and duration of the pilot study are discussed. Consideration is also given to the identification and collection of author characteristics hypothesized to affect publication decisions.

Serum cortisol levels were determined in 40 normal Chinese and dopamine beta-hydroxylase activities were measured in 22 normal subjects before and after acupuncture treatment. All subjects were studied twice with an interval of one week or more. In the self-control study, the subjects were needled at 5 non-acupuncture loci. in the experimental study, they were needled at the following 5 traditional acupuncture loci - right side GB-20, both sides EH-6, and both sides St-36. Blood samples were withdrawn before acupuncture and 15 and 45 min. after acupuncture. No change of serum dopamine beta-hydroxylase activity was observed. Serum cortisol levels increased significantly after needling on the traditional acupuncture loci. After acupuncture for 15 and 45 min., the cortisol increase was 28 and 50%, respectively, as compared to the self-control studies. The beneficial effect of acupuncture in the treatment of functional disorders, therefore, may be mediated by cortisol or other hormones and neurohormones.