title: Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study.

text: OBJECTIVE To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg. METHOD Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks. Subjects were enrolled between September 2006 and February 2010. Efficacy outcomes included predefined criteria for response, remission, recovery, relapse, and recurrence. Subjects treated with adjunctive L-methylfolate 15 mg were included in the efficacy analysis. RESULTS Of 68 subjects who met criteria for the 12-month open-label phase, 38% (n = 26) achieved full recovery, and none experienced a recurrence of MDD. For subjects entering the open-label phase in remission (n = 11), 91% (n = 10) achieved full recovery with L-methylfolate 15 mg, and none experienced a relapse or recurrence. Among 57 subjects who entered the open-label phase as nonremitted, 61% (n = 35) achieved remission. Of subjects who entered the open-label phase with a response without remission (n = 4), 50% (n = 2) had full recovery, and of subjects entering the open-label phase with no response (n = 53), 26% (n = 14) met recovery criteria. CONCLUSIONS Adjunctive L-methylfolate 15 mg/d may be an early option in patients who fail to adequately respond to antidepressant monotherapy, with preliminary evidence demonstrating sustained remission and sustained recovery. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00321152.


title: Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment.

text: The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines.


title: Health Care Provider Knowledge and Attitudes Regarding Reporting Diseases and Events to Public Health Authorities in Tennessee.

text: CONTEXT In the United States, state laws require health care providers to report specific diseases and events to public health authorities, a fundamental facet of disease surveillance. However, reporting by providers is often inconsistent, infrequent, and delayed. OBJECTIVE To examine knowledge, attitudes, and practices regarding provider disease reporting and to understand current barriers to provider disease reporting. DESIGN A cross-sectional study was conducted via an anonymous, standardized electronic survey. SETTING The survey was conducted at Vanderbilt University Medical Center, a large, tertiary academic medical center in Nashville, Tennessee. PARTICIPANTS Health care providers in 4 specialties (internal medicine, pediatrics, obstetrics-gynecology, and emergency medicine). MAIN OUTCOME MEASURE(S) Knowledge of and attitudes regarding provider reporting of diseases to public health authorities in Tennessee. RESULTS The majority of providers acknowledged they cared for patients with reportable diseases (362/435, 83.2%) and believed that it was their responsibility to report to public health authorities (429/436, 98.4%); however, less than half had ever reported a case (206/436, 47.2%). The median percent correct on the knowledge assessment of Tennessee reportable diseases and conditions was 81.3% (interquartile range = 68.8-87.5). Providers cited a lack of knowledge of which diseases are reportable (186/429, 43.3%) and the logistics of reporting (153/429, 35.7%) as the primary barriers for compliance. CONCLUSION Most providers acknowledged they cared for patients with reportable diseases and believed they had an obligation to report to public health authorities. However, a lack of knowledge about reporting was frequently described as a limitation to report effectively. Many knowledge deficits were significantly greater among residents than other providers.The policy and practice implications of these findings include a demonstrated need for education of providers about disease reporting as well as development of more convenient reporting mechanisms. Fundamental knowledge of reportable disease requirements and procedures is critical for participation in the broader public health system.


title: Treatment with octreotide does not reduce tumor uptake of (68)Ga-DOTATATE as measured by PET/CT in patients with neuroendocrine tumors.

text: UNLABELLED We hypothesized that (68)Ga-DOTATATE uptake of neuroendocrine tumors is sensitive to therapy with a nonradioactive somatostatin analog. METHODS (68)Ga-DOTATATE PET/CT was used to examine 105 patients, 35 of whom had been pretreated with long-acting octreotide. The maximum standardized uptake value (SUV(max)) of target tissues, as well as metastases, was compared between the groups of patients with (group 1) and without (group 2) octreotide treatment. RESULTS The SUV(max) of the spleen and liver was significantly lower in group 1 than in group 2 (both P < 0.001). There were no significant group differences in SUV(max) for primary tumors (28.6 ± 6.8 vs. 32.9 ± 31.5) or metastases in the liver (27.2 ± 14.8 vs. 25.7 ± 10.7), lymph nodes (41.4 ± 19.5 vs. 25.0 ± 6.3), or skeleton (39.5 ± 22.0 vs. 15.4 ± 7.8). In 9 patients available for intraindividual comparison, tumor uptake was unaffected by treatment with somatostatin analogs (21.7 vs. 20.6; P = 0.93). CONCLUSION Treatment with a long-acting somatostatin analog did not significantly reduce (68)Ga-DOTATATE binding in neuroendocrine tumors but tended to improve the tumor-to-background ratio.


title: Emergent Start Peritoneal Dialysis for End-Stage Renal Disease: Outcomes and Advantages.

text: BACKGROUND/AIMS Initiating renal replacement therapy in late referred patients with central venous catheter (CVC) hemodialysis (HD) causes serious complications. In urgent start peritoneal dialysis, initiating peritoneal dialysis (PD) within 14 days of catheter insertion still needs HD with CVC. We initiated Emergent start PD (ESPD) with Automated PD (APD) at our center within 48 h from the time of presentation. METHODS A prospective, case-controlled, intention-to-treat study with 56 patients was conducted between March 2016 and August 2017. Group A (24 patients) underwent conventional PD 14 days after catheter insertion. Group B (32 patients), underwent ESPD with APD. Exit site leak (ESL), catheter blockage, and peritonitis at 90 days were primary outcomes. Technique survival was secondary outcome. RESULTS Baseline characteristics were similar with 3 episodes of ESLs (9.4%) in the study group and none in the control group (p = 0.123). Catheter blockage (16.7%-Group A, 25%-Group B) and peritonitis (none vs. 9.4% in study group) were similar in terms of statistical details just as technique survival (95%-Group A, 88.2%-Group B at 90 days). CONCLUSION ESPD with APD in the unplanned patient is an appropriate approach.


title: Food waste disposal units in UK households: the need for policy intervention.

text: The EU Landfill Directive requires Member States to reduce the amount of biodegradable waste disposed of to landfill. This has been a key driver for the establishment of new waste management options, particularly in the UK, which in the past relied heavily on landfill for the disposal of municipal solid waste (MSW). MSW in the UK is managed by Local Authorities, some of which in a less conventional way have been encouraging the installation and use of household food waste disposal units (FWDs) as an option to divert food waste from landfill. This study aimed to evaluate the additional burden to water industry operations in the UK associated with this option, compared with the benefits and related savings from the subsequent reductions in MSW collection and disposal. A simple economic analysis was undertaken for different FWD uptake scenarios, using the Anglian Region as a case study. Results demonstrated that the significant savings from waste collection arising from a large-scale uptake of FWDs would outweigh the costs associated with the impacts to the water industry. However, in the case of a low uptake, such savings would not be enough to cover the increased costs associated with the wastewater provision. As a result, this study highlights the need for policy intervention in terms of regulating the use of FWDs, either promoting them as an alternative to landfill to increase savings from waste management, or banning them as a threat to wastewater operations to reduce potential costs to the water industry.


title: How the noninflammasome NLRs function in the innate immune system.

text: NLR (nucleotide-binding domain, leucine-rich repeat-containing) proteins have rapidly emerged as central regulators of immunity and inflammation with demonstrated relevance to human diseases. Much attention has focused on the ability of several NLRs to activate the inflammasome complex and drive proteolytic processing of inflammatory cytokines; however, NLRs also regulate important inflammasome-independent functions in the immune system. We discuss several of these functions, including the regulation of canonical and noncanonical NF-kappaB activation, mitogen-activated protein kinase activation, cytokine and chemokine production, antimicrobial reactive oxygen species production, type I interferon production, and ribonuclease L activity. We also explore the mechanistic basis of these functions and describe current challenges in the field.


title: Transumbilical scarless surgery with thoracic trocar: easy and low-cost.

text: PURPOSE Single-site laparoscopic surgery has become increasingly common. We herein report an easy and low-cost thoracic trocar technique (TTT) for these types of procedures and recommend the simpler name "transumbilical scarless surgery" (TUSS) to minimize confusion in nomenclature. METHODS We retrospectively reviewed patients who underwent TUSS by TTT using a thoracic trocar and surgical glove in our hospital between November 2011 and November 2012. Operating time, postoperative stay, and complications were detailed. RESULTS A total of 101 TUSS by TTT were successfully performed, comprising appendectomy (n = 63), ovarian cyst excision (n = 7), splenectomy (n = 5), nephroureterectomy (n = 5), orchidopexy (n = 4), pyeloplasty (n = 3), nephrolithotomy (n = 2), orchiectomy (n = 2), varicocelectomy (n = 2), lymphangioma excision (n = 2), ureterectomy (n = 1), Morgagni diaphragmatic hernia repair (n = 1), ovarian detorsion (n = 1), antegrade continence enema (n = 1), intestinal resection anastomosis (n = 1), and intestinal duplication excision (n = 1). Kirschner wires were used for some organ traction. Nine patients required an additional port, but no major complications occurred. The postoperative stay (mean ± standard deviation) was 3.2 ± 1.4 days, and operating time was 58.9 ± 38.3 minutes. CONCLUSION We recommend the simpler name of TUSS to minimize confusion in nomenclature for all transumbilical single-incision laparoendoscopic surgeries. TTT is an easy and low-cost TUSS technique.


title: Accuracy and precision of buccal pulse oximetry.

text: OBJECTIVE We sought to describe the accuracy and precision of buccal pulse oximetry (SbpO(2)) compared with arterial oxygen saturation (SaO(2)) and pulse oximetry (SpO(2)) in healthy adults at normoxemia and under 3 induced hypoxemic conditions. METHODS In this prospective, correlational study, SbpO(2), SaO(2), and SpO(2) values were recorded at normoxemia and at three hypoxemic conditions (SpO(2)=90%, 80%, and 70%) for 53 healthy, nonsmoking adults who were without cardiac or pulmonary disease, baseline hypoxemia, peripheral edema, dyshemoglobinemia, and fever. Bland-Altman analyses were used to assess agreement and precision between SbpO(2) and SaO(2) measures and between SbpO(2) and SpO(2) measures. Data were adjusted to account for a lag time between buccal and finger sites. RESULTS When comparing SbpO(2) and SaO(2) values, mean differences of -1.8%, .3%, 2.4%, and 2.6% were evident at the normoxemia, 90%, 80%, and 70% levels, respectively. When comparing SbpO(2) and SpO(2) values, the mean differences were -1.4%, .1%, 3.3%, and 4.7% at the normoxemia, 90%, 80%, and 70% levels, respectively. The SbpO(2) and SaO(2) values met a priori precision criteria (1.6%; 95% confidence limit, -4.9% to 1.3%) at normoxemia. The SbpO(2) and SpO(2) values met precision criteria at normoxemia (1.5%; 95% confidence limit, -4.4% to 1.5%) and 90% (1.9%; 95% confidence limit, -3.6% to 3.8%) conditions, but exceeded precision criteria at the other tested conditions. On average, SpO(2) lagged 21 seconds behind SbpO(2). CONCLUSION Buccal oximetry is an inaccurate and imprecise method of assessing SpO(2) when oxygen saturation is <90%. The divergence between SbpO(2) and both SaO(2) or SpO(2) values increased as hypoxemia worsened. The buccal method overestimated oxygen saturation in proportion to the degree of hypoxemia. Such overestimates may lead nurses to conclude falsely that a patient's arterial oxygen saturation is acceptable when further assessment or intervention is warranted.


title: Back to the Future: Principles on Resuming Outpatient Services in the COVID-19 Era.

text: The rapidly changing health care climate related to coronavirus disease 2019 (COVID-19) has resulted in numerous changes to health care systems and in practices that protect both the public and the workers who serve in hospitals around the country. As a result, these past few months have seen a drastic reduction in outpatient visits. With phased reopening and appropriate guidance, health care systems are attempting to return to normal. The experiences and lessons learned are described, and we provide guiding principles to allow for a safe and effective return to outpatient care.


Clonal spread of Geomyces destructans among bats, midwestern and southern United States.


title: Influence of Bayesian optimization on the performance of propofol target-controlled infusion.

text: Background Target controlled infusion (TCI) systems use population-based pharmacokinetic (PK) models that do not take into account inter-individual residual variation. This study compares the bias and inaccuracy of a population-based vs a personalized TCI propofol titration using Bayesian adaptation. Haemodynamic and hypnotic stability, and the prediction probability of alternative PK models, was studied. Methods A double-blinded, prospective randomized controlled trial of 120 subjects undergoing cardiac surgery was conducted. Blood samples were obtained at 10, 35, 50, 65, 75 and 120 min and analysed using a point-of-care propofol blood analyser. Bayesian adaptation of the PK model was applied at 60 min in the intervention group. Median (Absolute) Performance Error (Md(A)PE) was used to evaluate the difference between bias and inaccuracy of the models. Haemodynamic (mean arterial pressure [MAP], heart rate) and hypnotic (bispectral index [BIS]) stability was studied. The predictive performance of four alternative propofol PK models was studied. Results MdPE and MdAPE did not differ between groups during the pre-adjustment period (control group: 6.3% and 16%; intervention group: 5.4% and 18%). MdPE differed in the post-adjustment period (12% vs. -0.3%), but MdAPE did not (18% vs. 15%). No difference in heart rate, MAP or BIS was found. Compared with the other models, the Eleveld propofol PK model (patients) showed the best prediction performance. Conclusions When an accurate population-based PK model was used for propofol TCI, Bayesian adaption of the model improved bias but not precision. Clinical trial registration Dutch Trial Registry NTR4518.


title: Transumbilical pure single-port laparoscopic donor nephrectomy.

text: Transumbilical single-port laparoscopic donor nephrectomy (SPLDN) is a novel, rapidly evolving, minimally invasive treatment modality for kidney transplantation. This method causes minimal parietal injury, has cosmetic advantages, and allows rapid recovery because of low postoperative pain and short hospital stay. Like other abdominal surgeries, when conducted by experienced laparoscopic surgeons, it can meet the same graft requirements as conventional laparoscopic surgery. Here, we report the first two cases of transumbilical SPLDN at Daejeon St. Mary's Hospital, The Catholic University of Korea. We used the umbilicus as a common path for laparoscopic procedures and as a route for specimen retrieval. The operating times were 230 and 265 minutes in cases 1 and 2, respectively. No intra- or postoperative complications were noted. In case 1, the wound length was 4 cm and duration of hospitalization was 2 days. In case 2, the wound length was only 2.5 cm, and the duration of hospitalization was only 1 day.


title: Ebola virus modulates transforming growth factor β signaling and cellular markers of mesenchyme-like transition in hepatocytes.

text: UNLABELLED Ebola virus (EBOV) causes a severe hemorrhagic disease in humans and nonhuman primates, with a median case fatality rate of 78.4%. Although EBOV is considered a public health concern, there is a relative paucity of information regarding the modulation of the functional host response during infection. We employed temporal kinome analysis to investigate the relative early, intermediate, and late host kinome responses to EBOV infection in human hepatocytes. Pathway overrepresentation analysis and functional network analysis of kinome data revealed that transforming growth factor (TGF-β)-mediated signaling responses were temporally modulated in response to EBOV infection. Upregulation of TGF-β signaling in the kinome data sets correlated with the upregulation of TGF-β secretion from EBOV-infected cells. Kinase inhibitors targeting TGF-β signaling, or additional cell receptors and downstream signaling pathway intermediates identified from our kinome analysis, also inhibited EBOV replication. Further, the inhibition of select cell signaling intermediates identified from our kinome analysis provided partial protection in a lethal model of EBOV infection. To gain perspective on the cellular consequence of TGF-β signaling modulation during EBOV infection, we assessed cellular markers associated with upregulation of TGF-β signaling. We observed upregulation of matrix metalloproteinase 9, N-cadherin, and fibronectin expression with concomitant reductions in the expression of E-cadherin and claudin-1, responses that are standard characteristics of an epithelium-to-mesenchyme-like transition. Additionally, we identified phosphorylation events downstream of TGF-β that may contribute to this process. From these observations, we propose a model for a broader role of TGF-β-mediated signaling responses in the pathogenesis of Ebola virus disease. IMPORTANCE Ebola virus (EBOV), formerly Zaire ebolavirus, causes a severe hemorrhagic disease in humans and nonhuman primates and is the most lethal Ebola virus species, with case fatality rates of up to 90%. Although EBOV is considered a worldwide concern, many questions remain regarding EBOV molecular pathogenesis. As it is appreciated that many cellular processes are regulated through kinase-mediated phosphorylation events, we employed temporal kinome analysis to investigate the functional responses of human hepatocytes to EBOV infection. Administration of kinase inhibitors targeting signaling pathway intermediates identified in our kinome analysis inhibited viral replication in vitro and reduced EBOV pathogenesis in vivo. Further analysis of our data also demonstrated that EBOV infection modulated TGF-β-mediated signaling responses and promoted "mesenchyme-like" phenotypic changes. Taken together, these results demonstrated that EBOV infection specifically modulates TGF-β-mediated signaling responses in epithelial cells and may have broader implications in EBOV pathogenesis.


Covid-19 and Diabetes in Hawaii.


How to turn competitors into collaborators.


title: Managing the apparent and hidden difficulties of weaning from mechanical ventilation.

text: BACKGROUND In anaesthetized patients scheduled for surgery, tracheal intubation is performed with the expectation of subsequent smooth extubation. In critically ill patients, separation from the ventilator is often gradual and the time chosen for extubation may be either delayed or premature. Thus, weaning is challenging, represents a large part of the ventilation period and concerns all mechanically ventilated patients surviving their stay. DEFINITIONS AND MANAGEMENT Weaning may be stratified in three groups according to its difficulty and duration. In simple weaning the main issue is to detect the soonest time to start separation from the ventilator; this is frequently impeded by poor sedation management and excessive ventilator assistance. A two-step diagnostic approach is the most efficacious: screening for ascertained readiness to wean is confirmed by a diagnostic test simulating the post-extubation period, best performed by unassisted breathing (no PEEP). In case of test failure (difficult weaning), a structured and thorough diagnostic work-up regarding potentially reversible pathologies is required with a focus on cardiovascular dysfunction or fluid overload at the time of separation from the ventilator, respiratory or global muscle weakness and underlying infection. Prolonged weaning is exceptionally time- and resource-consuming, needs to properly appraise psychological problems, sleep and nutrition, and is probably best performed in specialized units. CONCLUSIONS Adequately managing simple and difficult weaning requires one to think about ICU policies in terms of sedation, fluid balance and having a systematic screening strategy; it also needs an individualized approach to understand and treat the failing patients. Prolonged weaning requires a holistic approach.


title: Dexamethasone contributes to the patient management after ambulatory laryngeal microsurgery by reducing sore throat.

text: This study was planned to evaluate the preventive effect of dexamethasone for sore throat after ambulatory laryngeal microsurgery. One hundred and ten patients scheduled for ambulatory laryngeal microsurgery under general anesthesia were randomly divided into two groups, group S1 and group D1. Patients in the group D1 were injected with 0.2 mg/kg of intravenous dexamethasone before the induction of anesthesia. The incidences and severities of sore throat were measured using verbal rating scale (VRS) at 1 h and through phone calls at 6 h after the operation. The patients who requested analgesics in the recovery room were measured VRS shortly before administration of medicine. The patients in group S1 and group D1 who did not receive rescue analgesics were enrolled in group S6 and group D6, respectively, and evaluated 6 h after the surgery. There were no significant differences in the incidence and severity scores of sore throat during 1 h after the end of operation between group S1 and group D1. But at 6 h, the patients in the group D6 had lower incidence of sore throat than those in group S6 significantly (P = 0.003). Furthermore, the patients in the group D6 had lower severity of sore throat than those in group S6 significantly at 6 h (P = 0.001). In conclusion, prophylactic administration of intravenous dexamethasone is appeared to have efficacy for the management of sore throat in the early post-discharge period following ambulatory laryngeal microsurgery.


Covid-19: research methods must be flexible in a crisis.


Missing the Target.


Future perfect? Improving preparedness through the experiences of the influenza A (H1N1) 2009 pandemic.


title: Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?

text: OBJECTIVE Degeneration of oligodendroglial distal processes has been identified as an early event in multiple sclerosis (MS) lesion development. Our objective was to further define the development of the "dying-back" oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain-derived oligodendrocytes. METHODS In situ analyses were performed on glutaraldehyde-fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain-derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose). RESULTS In situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction, which was linked to reduced glycolytic respiratory activity, is reversible until a critical time point. Subsequent cell death was not linked to caspase-3-dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity. INTERPRETATION Our findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies of the mechanisms underlying subsequent adult human oligodendrocyte cell death. Ann Neurol 2017;81:811-824.


title: Microcirculation measured by vascular occlusion test during desflurane-remifentanil anesthesia is superior to that in propofol-remifentanil anesthesia in patients undergoing thoracic surgery: subgroup analysis of a prospective randomized study.

text: General anesthesia can affect microcirculatory properties. However, differential effects on the microcirculation according to the anesthetic technique used during thoracoscopic surgery have not been well documented. We conducted a randomized clinical trial in which the effects of desflurane and propofol, both with remifentanil, on systemic arterial oxygenation during one-lung ventilation were compared in patients undergoing thoracoscopic surgery. As a subgroup analysis, we compared the effects of two commonly used anesthetic techniques, desflurane-remifentanil (n = 52) and propofol-remifentanil (n = 48), on tissue oxygen saturation using a vascular occlusion test in patients undergoing thoracoscopic surgery. Tissue oxygen saturation was higher in the desflurane than the propofol group (mean ± standard deviation, 83 ± 6 vs. 80 ± 9, 84 ± 6 vs. 76 ± 10, and 87 ± 7 vs. 77 ± 10 % at 30 and 60 min of one-lung ventilation and at two-lung ventilation; adjusted p = 0.026, <0.001, and <0.001, respectively). The recovery slope during the vascular occlusion test, reflecting microvascular reperfusion adequacy, was higher in the desflurane than the propofol group during surgery (mean difference, 0.5 %/s; 95 % CI 0.0-0.9 %/s; p = 0.037). Desflurane-remifentanil anesthesia is associated with better microcirculation than propofol-remifentanil anesthesia in patients undergoing thoracoscopic surgery.


title: Impact of anesthesia on mortality during endovascular clot removal for acute ischemic stroke.

text: BACKGROUND Endovascular clot retrieval is a technique available for removing intracranial arterial occlusions in acute ischemic stroke (AIS). This rescue therapy can be performed with moderate conscious sedation (CS) or general anesthesia (GA). The effect of GA on clinical outcome in AIS remains controversial. Therefore, we retrospectively investigated whether the use of CS or GA during endovascular intervention for AIS influenced outcomes. METHODS Patients who underwent emergent endovascular intervention for intracranial arterial occlusion during the years 2006 to 2012 were included in this study. Statistical analysis using the Spearman ρ was performed to examine demographic data and clinical outcomes between patients in the GA and CS groups. Binary logistic regression was used to determine the predictors of mortality. RESULTS A total of 109 patients fit the inclusion criteria. Among them, 35 patients had GA and 74 patients had CS. Patients needing intubation upon admission for airway protection were more likely to receive GA (P<0.001). The duration of the procedure and the time-to-revascularization from symptom onset were significantly longer in the GA group. Mortality was higher in the GA group compared with the CS group (40% vs. 22%, P=0.045). Multivariate analysis, controlled for confounding variables, identified GA and elevated postprocedure glucose level to be significant predictors of mortality. CONCLUSIONS Larger prospectively randomized multicenter trials evaluating the effects of GA and CS on clinical and radiographic outcomes seems warranted.


title: The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique.

text: Clinical signs are unreliable for guiding anaesthetic administration and it is suggested that using the bispectral index can improve anaesthetic delivery. In the current study, isoflurane administration was guided to a bispectral index range of 55-60. Intra-operative responsiveness, as assessed by the isolated forearm technique, was compared with whether the bispectral index predicted/identified a patient's appropriate hand movements in response to commands. Thirty-four women underwent major gynaecological surgery with isoflurane/air and atracurium. Eleven women responded on 32 occasions with appropriate hand movements to commands given during surgery, of which the bispectral index detected 17 (sensitivity 53%). The bispectral index suggested consciousness 660 times in the absence of any movement responses (specificity 69%). The positive predictive value of the bispectral index was 3%. The median (IQR [range]) bispectral index value associated with an intra-operative response was significantly lower than that associated with eye opening after surgery: 60 (50-68 [36-83]) vs 77 (75-84 [59-90]), respectively (p = 2.25 × 10(-8)). Conversely, end-tidal isoflurane concentration was significantly higher at intra-operative response than at eye opening: 0.3 (0.3-0.4 [0.2-0.9]) vs 0.2 (0.1-0.2 [0.1-0.3]), respectively (p = 7.36 × 10(-8)). For patients who responded more than once during surgery, the bispectral index value associated with a response was not constant. No patient had recall for surgery or the taped commands, and only one could remember dreaming (a good dream). Titrating isoflurane to target a bispectral index range of 55-60 may result in an unacceptable number of patients who are conscious during surgery (albeit without recall).


title: Evolution in health and medicine Sackler colloquium: The comparative genomics of viral emergence.

text: RNA viruses are the main agents of emerging and re-emerging diseases. It is therefore important to reveal the evolutionary processes that underpin their ability to jump species boundaries and establish themselves in new hosts. Here, I discuss how comparative genomics can contribute to this endeavor. Arguably the most important evolutionary process in RNA virus evolution, abundant mutation, may even open up avenues for their control through "lethal mutagenesis." Despite this remarkable mutational power, adaptation to diverse host species remains a major adaptive challenge, such that the most common outcome of host jumps are short-term "spillover" infections. A powerful case study of the utility of genomic approaches to studies of viral evolution and emergence is provided by influenza virus and brought into sharp focus by the ongoing epidemic of swine-origin H1N1 influenza A virus (A/H1N1pdm). Research here reveals a marked lack of surveillance of influenza viruses in pigs, coupled with the possibility of cryptic transmission before the first reported human cases, such that the exact genesis of A/H1N1pdm (where, when, how) is uncertain.


title: Single-stage bilateral thoracic surgery via a combined VATS and open approach for left central bronchogenic carcinoma with carinal invasion: report of two cases.

text: BACKGROUND Surgery for patients with left central bronchogenic carcinoma invading the carina is challenging due to the complexity of left sleeve pneumonectomy, carinal resection, and airway reconstruction and management. Here we describe a modified approach to overcome this problem. CASE PRESENTATION Between March 2011 and September 2012, two patients with left central bronchogenic carcinoma invading the carina underwent single-stage bilateral thoracic surgery via a combined approach incorporating video-assisted thoracic surgery (VATS) and thoracotomy in our hospital. We reviewed our experience with this type of surgery and analyze its outcomes. CONCLUSIONS Single-stage, bilateral thoracic surgery incorporating video assisted thoracic surgery (VATS) and thoracotomy provides optimal exposure of the operative field, reduces surgical trauma, and ensures the integrity of tumor excision and exactness of tracheobronchial anastomosis. This may be a safe and feasible alternative for left carinal pneumonectomy.


Video-assisted thoracoscopic lobectomy using a standardized three-port anterior approach - The Copenhagen experience.


Is mandatory vaccination legal in time of epidemic?


title: Cross-species transmission of poultry pathogens in backyard farms: ducks as carriers of chicken viruses.

text: In backyard farms of Lao People's Democratic Republic, mixed-species rearing of poultry is a breeding-ground for cross-species transmission. Here, the epidemiology of viruses circulating among backyard poultry in Vientiane Province was assessed to guide future control strategies. Oral/tracheal and cloacal swabs, collected from 605 poultry (308 ducks, 297 chickens) between 2011 and 2015, were screened by PCR for Newcastle disease virus (NDV), Coronavirus (CoV) and Chicken Anemia Virus (CAV). Chicken sera were screened for anti-NDV antibodies by ELISA. Statistical and phylogenetic analyses revealed transmission patterns and relationships. Closely related strains co-circulated in chickens and ducks. While CoV RNA was detected in oral/tracheal swabs of 9.3% of the chickens and 2.4% of the ducks, rates were higher in fecal swabs of both species (27.3% and 48.2%). RNA of Infectious bronchitis virus (IBV) and duck CoV was found in fecal swabs of chickens (19.7% and 7.1%) and of ducks (4.1% and 44.1%). Moreover, DNA of the generally chicken-specific CAV was detected in oral/tracheal swabs of chickens (18.1%) and sporadically of ducks (2.4%). Despite serological evidence of NDV circulation or vaccination (86.9%), NDV RNA was not detected. We found a high prevalence and indication for cross-species transmission of different CoV strains in backyard poultry. Interestingly, ducks served as biological or at least mechanical carrier of viral strains closely related not only to IBV, but also to CAV. Animal containment and poultry species separation could be first steps to avoid cross-species transmission and emergence of novel strains with broad host range and enhanced pathogenicity.


title: Identification and Monitoring of International Travelers During the Initial Phase of an Outbreak of COVID-19 - California, February 3-March 17, 2020.

text: The threat of introduction of coronavirus disease 2019 (COVID-19) into the United States with the potential for community transmission prompted U.S. federal officials in February 2020 to screen travelers from China, and later Iran, and collect and transmit their demographic and contact information to states for follow-up. During February 5-March 17, 2020, the California Department of Public Health (CDPH) received and transmitted contact information for 11,574 international travelers to 51 of 61 local health jurisdictions at a cost of 1,694 hours of CDPH personnel time. If resources permitted, local health jurisdictions contacted travelers, interviewed them, and oversaw 14 days of quarantine, self-monitoring, or both, based on CDC risk assessment criteria for COVID-19. Challenges encountered during follow-up included errors in the recording of contact information and variation in the availability of resources in local health jurisdictions to address the substantial workload. Among COVID-19 patients reported to CDPH, three matched persons previously reported as travelers to CDPH. Despite intensive effort, the traveler screening system did not effectively prevent introduction of COVID-19 into California. Effectiveness of COVID-19 screening and monitoring in travelers to California was limited by incomplete traveler information received by federal officials and transmitted to states, the number of travelers needing follow-up, and the potential for presymptomatic and asymptomatic transmission. More efficient methods of collecting and transmitting passenger data, including electronic provision of flight manifests by airlines to federal officials and flexible text-messaging tools, would help local health jurisdictions reach out to all at-risk travelers quickly, thereby facilitating timely testing, case identification, and contact investigations. State and local health departments should weigh the resources needed to implement incoming traveler monitoring against community mitigation activities, understanding that the priorities of each might shift during the COVID-19 pandemic.


title: Pyogranulomatous cystitis associated with Toxoplasma gondii infection in a cat after renal transplantation.

text: CASE DESCRIPTION An 8-year-old spayed female domestic shorthair cat was evaluated for azotemia and a suspected mass in the urinary bladder 6 weeks after receiving a renal transplant. Ultrasonography revealed a mass at the ureteroneocystostomy site, and the mass was excised. Both the donor and recipient cats were seronegative for Toxoplasma gondii-specific IgG antibodies prior to transplantation. CLINICAL FINDINGS Histologic evaluation of the mass revealed lesions indicative of extensive necrotizing pyogranulomatous cystitis with numerous intralesional T gondii tachyzoites and bradyzoite cysts. TREATMENT AND OUTCOME Treatment with clindamycin was initiated; however, the cat's clinical condition continued to decline, and it was euthanized 9 days after the mass was excised. Necropsy revealed T gondii cysts within the renal allograft and the transplanted ureter, with no evidence of systemic spread of organisms. CLINICAL RELEVANCE Toxoplasmosis should be considered as a differential diagnosis for azotemia in feline renal transplant recipients regardless of the results of assays for T gondii antibodies in the serum of donors or recipients. This report illustrated the need for improved screening of donor and recipient cats and the importance of minimizing exposure to potential sources of T gondii after transplantation.


title: Totally minimally invasive Ivor-Lewis esophagectomy with single-utility incision video-assisted thoracoscopic surgery for treatment of mid-lower esophageal cancer.

text: The study aims to evaluate the safety and availability of totally minimally invasive Ivor-Lewis esophagectomy (MIIE) with single-utility incision video-assisted thoracoscopic surgery. Forty-one patients with mid-lower thoracic esophageal cancer were prospectively treated with totally MIIE. Two stages of laparoscopic-thoracoscopic procedures were performed. The first 29 patients were treated with four-port video-assisted thoracoscopic surgery (Group 1); the others were treated with single-utility incision video-assisted thoracoscopic surgery (Group 2). Short-term clinicopathological outcomes were examined. All patients had negative tumor margins and were pathologically staged from T1N0M0 to T3N2M0. Among Group 1, there was one conversion to open surgery. The mean duration of surgery was 268.4 ± 37.8 minutes, and mean blood loss was 207.2 ± 74.1 mL without significant differences between groups. The average thoracic or abdominal lymph node yield was 12.6 ± 7.1 or 6 ± 5.8, respectively. The median postoperative hospital stay was 7 days. No mortalities occurred. Minor morbidity complicated by late-stage gastroparesis occurred in two patients (4.9%) after discharge. Major morbidities, including intestinal obstruction and anastomotic leakage, occurred in three patients (7.3%) after discharge. Among Group 2, the average operative duration was 275.4 ± 31.2 minutes, and the mean blood loss was 220 ± 94.9 mL. One patient developed late-stage anastomotic leakage. The average thoracic or abdominal lymph node yield was 14.7 ± 8.8 and 6.3 ± 5.7, respectively. No statistically significant differences were identified between Group 1 and Group 2. MIIE with single-utility incision video-assisted thoracoscopic surgery is feasible in patients with mid-lower thoracic esophageal cancer without compromising the extent of surgical resection and perioperative outcomes.


title: The BMA COVID-19 ethical guidance: a legal analysis.

text: The paper considers the recently published British Medical Association Guidance on ethical issues arising in relation to rationing of treatment during the COVID-19 Pandemic. It considers whether it is lawful to create policies for the rationing and withdrawal of treatment, and goes on to consider how such policies might apply in practice. Legal analysis is undertaken of certain aspects of the Guidance which appear to misunderstand the law in respect of withdrawing treatment.


WHO warns that averting flu pandemic may be harder as surveillance switches to covid-19.


title: Air pollution and COVID-19: Is the connect worth its weight?

text: Primary route of transmission of SARS-CoV-2 among humans is droplets and direct contact. Airborne transmission of this virus is not established conclusively and so is the role of airborne particulate matter. This commentary examines the existing evidence about the role of particulate matter pollutants in SARS-CoV-2 transmission. PM2.5and other small particulate matter have been shown to carry viable virus particles in the air and incriminated in spread of measles and SARS coronavirus. Empirical evidence has been provided regarding role of air pollution in accelerated transmission of SARS-CoV-2 in Italy as well as Wuhan. Lockdown-related reduction in PM2.5levels in ambient air may have contributed to reduce transmission of SARS-CoV-2. High PM2.5levels in the past might have added to SARS-CoV-2 related mortality due to air pollution relate comorbidities. Post-lockdown increase in PM2.5levels may accelerate covid-19 transmission and can add to the burden of COVID-19 morbidity and mortality.


title: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review.

text: Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.


title: [First case of COVID-19 treated with tocilizumab in Iceland].

text: A gentleman in his early fifties became ill with flu-like symptoms after vacationing abroad and was diagnosed with COVID-19 after returning to Iceland. A few days later he was admitted to the University Hospital, Landspitali, due to worsening respiratory symptoms and severe fatigue. A computed tomography scan of lthe lungs showed diffuse bilateral consolidations and ground glass changes. He developed respiratory failure and was transferred to the intensive care unit where he received further treatment, including tocilizumab (IL-6 receptor inhibitor). He subsequently showed clinical improvement and did not require endotracheal intubation.


title: Aquatic cycling-What do we know? A scoping review on head-out aquatic cycling.

text: Over the past few years, aquatic cycling has become a trending fitness activity. However, the literature has not been reviewed exhaustively. Therefore, using scoping review methodology, the aim of this review was to explore the current state of the literature concerning aquatic cycling. This study specifically focused on study designs, populations and outcomes. A comprehensive search of seven databases (PubMed, MEDLINE, Cinahl, Embase, PEDro,Web of Science, WorldCat) was conducted up to 30th September 2016. GoogleScholar, World Cat, ResearchGate, specific aquatic therapy websites and aquatic therapy journals were searched to identify additional literature. Full-text publications in English, German or Dutch were included. Studies were included when the intervention involved head-out cycling carried out in 10° to 35° Celsius water. Exclusion criteria were the use of wet suits or confounding interventions that would affect participants' homeostasis. 63 articles were included and the study parameters of these studies were summarized. Using three grouping themes, included studies were categorised as 1) single session tests comparing aquatic versus land cycling, or 2) aquatic cycling only sessions investigating different exercise conditions and 3) aquatic cycling intervention programmes. Although the experimental conditions differed noticeably across the studies, shared characteristics were identified. Cardiovascular parameters were investigated by many of the studies with the results suggesting that the cardiac demand of aquatic cycling seems similar to land-based cycling. Only six studies evaluated the effect of aquatic cycling interventions. Therefore, future research should investigate the effects of aquatic cycling interventions, preferably in individuals that are expected to gain health benefits from aquatic cycling. Moreover, this comprehensive outline of available literature could serve as a starting point for systematic reviews or clinical studies on the effects of aquatic cycling on the cardiovascular responses.


title: Per anal endoscopic rectopexy for treatment of complete rectal prolapse: A preliminary report.

text: We describe Per Anal Endoscopic Rectopexy (PAER), a new treatment for complete rectal prolapse, which involves fixing the anterior rectal wall to the under-surface of the anterior abdominal wall and posterior rectal wall to the sacrum, through a submucosal tunnel (both endoluminally). This is a prospective single-centre pilot study done at a tertiary care centre. A total of 12 patients with a mean age of 48 years underwent the procedure. Constipation and incontinence were present in 8 and 4 patients, respectively and a significant improvement was seen in both following the procedure. A significant decrease in anorectal angle and its descent was also observed on post procedure magnetic resonance defecography. One patient had partial recurrence of prolapse. No major morbidity was observed. PAER is a minimally invasive and safe option for rectal prolapse, which needs to be validated in more patients over a longer follow up period.


title: Two palmitylated cysteine residues of the severe acute respiratory syndrome coronavirus spike (S) protein are critical for S incorporation into virus-like particles, but not for M-S co-localization.

text: The endodomain of several coronavirus (CoV) spike (S) proteins contains palmitylated cysteine residues and enables co-localization and interaction with the CoV membrane (M) protein. Depalmitylation of mouse hepatitis virus S proteins abolished this interaction, resulting in the failure of S incorporation into virions. In contrast, an immunofluorescence assay (IFA) showed that depalmitylated severe acute respiratory syndrome coronavirus (SCoV) S proteins still co-localized with the M protein in the budding site. Here, we determined the ability of depalmitylated SCoV S mutants to incorporate S into virus-like particles (VLPs). IFA confirmed that all SCoV S mutants co-localized with the M protein intracellularly. However, the mutants lacking two cysteine residues (C(1234/1235)) failed to incorporate S into VLPs. This indicated that these palmitylated cysteines are essential for S incorporation, but are not involved in S co-localization mediated by the M protein. Our findings suggest that M-S co-localization and S incorporation occur independently of one another in SCoV virion assembly.


title: Stable mammalian producer cell lines for structural biology.

text: The mammalian cell lines HEK293 and CHO have become important expression hosts in structural biology. Generating stable mammalian cell lines remains essential for studying the function and structure of recombinant proteins, despite the emergence of highly efficient transient transfection protocols. Production with stable cell lines can be scaled up easily and high volumetric product yield can be achieved. Protein structure reports of the past two years that used stable cell lines were surveyed for this review. Well-established techniques and novel approaches for generating stable cell lines and stable cell pools are presented, including cell sorting, site-specific recombination, transposons, the Lentivirus system and phage integrases. Host cell line optimization by endoglycosidase overexpression and sequence-specific genome engineering is highlighted.


title: An 81 nucleotide deletion in SARS-CoV-2 ORF7a identified from sentinel surveillance in Arizona (Jan-Mar 2020).

text: On January 26 2020, the first Coronavirus Disease 2019 (COVID-19) case was reported in Arizona (3rd case in the US) (1).….


title: Villous mucinous cystadenoma of the appendix in a postmenopausal woman.

text: OBJECTIVE To present the case of a postmenopausal woman, who was suspected of having an ovarian cyst. Instead, a cystadenoma of the appendix was discovered during laparoscopy. METHODS A 64-year-old postmenopausal nulliparous woman was admitted to our hospital because of a cystic lesion, which had been detected in the course of a routine gynecological examination. The patient underwent vaginal ultrasound, magnetic resonance tomography, and laparoscopy. RESULTS During vaginal ultrasound, a dumbbell-shaped anechogenic cystic structure 70 x 32 x 22 mm in diameter was found in the region of the right adnexa. Magnetic resonance tomography revealed no additional information. During diagnostic laparoscopy, the cystic lesion was found to be a distended appendix. A laparoscopic appendectomy was performed. Subsequent histological analysis revealed a villous mucinous cystadenoma of the appendix with low-grade intraepithelial neoplasia. CONCLUSION Gynecologists should routinely consider this disease in the differential diagnosis of right lower dumbbell abdominal cysts. Eleven percent to 20% of mucoceles are caused by mucinous cystadenocarcinomas, which carry the risk of peritoneal tumor implantation caused by rupture or laparoscopic resection. Therefore, it should be mandatory that a general surgeon be involved in the laparoscopic procedure and the conversion to laparotomy for resection of the structure.


title: Reduction in distal emboli with proximal flow control during mechanical thrombectomy: a quantitative in vitro study.

text: BACKGROUND AND PURPOSE To evaluate the impact of proximal flow control on efficacy and safety of mechanical thrombectomy in an in vitro middle cerebral artery occlusion. METHODS Three independent variables, including clot type, device (Merci Retriever, Solitaire FR, and Trevo devices), and use of a balloon guide catheter, were used to ascertain the impact of proximal flow control on the size and number of distal emboli generated during thrombectomy. Secondary end points were the recanalization rate and amount of flow restored. RESULTS Use of the balloon guide catheter during thrombectomy of the fragile, hard clot significantly reduced the formation of large distal emboli with a diameter >1 mm, regardless of the device used (P<0.01). Applying aspiration via the balloon guide catheter in place of the conventional guide catheter resulted in a significant increase of flow reversal (P<0.0001). Prior to thrombectomy, deployment of the stent-trievers produced immediate flow restoration through the soft and hard clot occlusions, 69.2 ± 27.3 and 45.5 ± 22.8 mL/min, respectively, that was preserved after the balloon inflation because of collateral flow via the posterior communication artery. After deployment but before thrombectomy, no flow was restored when using the Merci Retriever. After thrombectomy, complete flow restoration was achieved in a majority of cases. The Merci Retriever required more thrombectomy attempts to achieve hard clot removal compared with the stent-trievers when the conventional guide catheter was used (1.5 versus 1.1). CONCLUSIONS The risk of distal embolization was significantly reduced with the use of the balloon guide catheter.


Machine learning can help get COVID-19 aid to those who need it most.


title: Harnessing the Digital Exhaust: Incorporating wellness into the pharma model.

text: The increasing availability of devices capable of tracking biomarkers presents major opportunities in contemporary healthcare. Herein we advocate a new role for the pharmaceutical industry to capitalize on these opportunities and in doing so incorporate wellness and patient engagement programs into their standard business models. Medical grade decision making using diagnostic, prognostic, and monitoring biomarkers will require coordinated approaches between the pharmaceutical and technology industries and the careful design of longitudinal clinical studies to validate their efficacy. These studies will also require data capture, archiving, curating and sharing on a previously unprecedented scale, and raise additional concerns with regard to data security and ownership. Concurrently, systems-based approaches to the capture and interpretation of a new class of digital biomarkers are emerging, and hold promise for heightened levels of patient engagement and remote sensing. Collectively, if these new opportunities are approached within the context of the patient-provider ecosystem, major repositioning of the pharmaceutical industry may be possible in the near term.


title: Spike protein, S, of human coronavirus HKU1: role in viral life cycle and application in antibody detection.

text: We recently described the discovery, genome, clinical features, genotypes and evolution of a novel and global human respiratory virus named human coronavirus HKU1 (HCoV-HKU1) which is not yet culturable. We expressed a C-terminal FLAG-tagged CoV-HKU1 spike (S) protein by the Semliki Forest Virus (SFV) system and investigated its maturation profile. Pulse chase labeling revealed that S-FLAG was expressed as high-mannose N-glycans of monomers and trimers. It was predominantly cleaved into subdomains S1 and S2 during maturation. S1 was secreted into the medium. Immunofluorescence analysis visualized S along the secretory pathway from endoplasmic reticulum to plasma membrane. Cleavage of S and release of HCoV-HKU1 S pseudotyped virus were inhibited by furin or furin-like enzyme inhibitors. The cell-based expressed full-length S-FLAG could be recognized by the convalescent serum obtained from a patient with HCoV-HKU1 pneumonia. The data suggest that the native form of HCoV-HKU1 spike expressed in our system can be used in developing serological diagnostic assay and in understanding the role of S in the viral life cycle.


title: Quantifying the cost of laparoscopic inguinal hernia repair.

text: BACKGROUND Laparoscopic inguinal hernia repair has been widely adopted. While the clinical advantages and disadvantages are well-quantified, the economic cost is less well-studied. METHODS A retrospective audit and case review of a single-centre public hospital consecutive case series was performed using data captured from real-time stock usage tracking technology and review of electronic medical records. RESULTS Laparoscopic inguinal hernia repair requires 11-min (21%) extra theatre time and costs $1268 (370%) more for single-use disposable equipment and prostheses. CONCLUSIONS Laparoscopic inguinal hernia repair does not require significantly more theatre time, but has a higher short-term in-hospital cost. Repair technique should be tailored according to patient factors.


title: Simulation-guided preparations for the management of suspected or confirmed COVID-19 cases in the obstetric emergency theater.

text: Aims: The coronavirus 2019 infection (COVID-19) global outbreak has resulted in unprecedented pressures on health services, the need to prepare for the worst-case scenario, and the need for health experts to utilize their knowledge and expertise to fight this virus. The simulation training objective of this study was to enhance the neonatal, maternity, and anesthetics teams' preparedness for the management of the emergency delivery of pregnant women with suspected or confirmed COVID-19 infection.Methods: Three clinical simulation training sessions were conducted in March 2020 at the University Hospital Plymouth, Plymouth, UK. The neonatal, maternity, and anesthetics clinical teams participated in these joint training sessions in the obstetric emergency theater.Results: Each session lasted for around an hour. Suggestions were discussed and recommendations made. The key changes were: first, floor plan adjustment, increase of the clinical area by converting some offices to clinical spaces, and standard operating procedures for transporting patients; second, enhancement of the efficiency of the communication and coordination between the clinical teams; third, availability of extra support for the staff in the Central Delivery Suite (CDS); and fourth, introduction of a neonatal care pathway to manage neonatal resuscitation in such an emergency.Conclusions: Collaboration and joint training between the different clinical teams involved in the care of suspected or confirmed COVID-19 patients was proven to be one of the most effective ways of improving performance.


title: Shotgun proteomics analysis of SARS-CoV-2-infected cells and how it can optimize whole viral particle antigen production for vaccines.

text: Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in a pandemic and is continuing to spread rapidly around the globe. No effective vaccine is currently available to prevent COVID-19, and intense efforts are being invested worldwide into vaccine development. In this context, all technology platforms must overcome several challenges resulting from the use of an incompletely characterized new virus. These include finding the right conditions for virus amplification for the development of vaccines based on inactivated or attenuated whole viral particles. Here, we describe a shotgun tandem mass spectrometry workflow, the data produced can be used to guide optimization of the conditions for viral amplification. In parallel, we analysed the changes occurring in the host cell proteome following SARS-CoV-2 infection to glean information on the biological processes modulated by the virus that could be further explored as potential drug targets to deal with the pandemic.


title: Motor adaptations to unilateral quadriceps fatigue during a bilateral pedaling task.

text: This study was designed to investigate how motor coordination adapts to unilateral fatigue of the quadriceps during a constant-load bilateral pedaling task. We first hypothesized that this local fatigue would not be compensated within the fatigued muscles leading to a decreased knee extension power. Then, we aimed to determine whether this decrease would be compensated by between-joints compensations within the ipsilateral leg and/or an increased contribution of the contralateral leg. Fifteen healthy volunteers were tested during pedaling at 350 W before and after a fatigue protocol consisting of 15 minutes of electromyostimulation on the quadriceps muscle. Motor coordination was assessed from myoelectrical activity (22 muscles) and joint powers calculated through inverse dynamics. Maximal knee extension torque decreased by 28.3%±6.8% (P<.0005) immediately after electromyostimulation. A decreased knee extension power produced by the ipsilateral leg was observed during pedaling (-22.8±12.3 W, -17.0%±9.4%; P<.0005). To maintain the task goal, participants primarily increased the power produced by the non-fatigued contralateral leg during the flexion phase. This was achieved by an increase in hip flexion power confirmed by a higher activation of the tensor fascia latae. These results suggest no adjustment of neural drive to the fatigued muscles and demonstrate no concurrent ipsilateral compensation by the non-fatigued muscles involved in the extension pedaling phase. Although interindividual variability was observed, findings provide evidence that participants predominantly adapted by compensating with the contralateral leg during its flexion phase. Both neural (between legs) and mechanical (between pedals) couplings and the minimization of cost functions might explain these results.


title: Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia.

text: BACKGROUND Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length. METHODS We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia. FINDINGS Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39-40 weeks (RR 1·12, 95% CI 1·12-1·13), by 19% for each 500 g reduction in birthweight less than 3000-3500 g (1·19, 1·18-1·21), and by 41% for each 5 cm reduction in birth length less than 45-50 cm (1·41, 1·38-1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st-5th percentile RR 1·15, 95% CI 1·12-1·19, and 1·11, 1·07-1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st-5th percentile RR 1·08, 95% CI 1·04-1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital. INTERPRETATION Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common. FUNDING Australian National Health and Medical Research Council.


Audio Interview: Approaches to Covid-19 Vaccines and Antivirals.


Junior researchers hit by coronavirus-triggered hiring freezes.


title: A New Aneurysm Occlusion Classification after the Impact of Flow Modification.

text: A new classification is proposed for cerebral aneurysms treated with any endovascular technique, for example, coiling with or without adjunctive devices, flow diversion, intrasaccular flow modifiers, or any combination of the above. Raymond-Roy Occlusion Classification is expanded with novel subgroups such as class 1 represents complete occlusion and is subdivided if a branch is integrated to, or originated from, the aneurysm sac; class 2 represents neck filling; class 3 represents incomplete occlusion with aneurysm filling as in the previous classification; and class 4 describes the immediate postoperative status after extra- or intrasaccular flow modification treatment. A new concept, "stable remodeling," is included as class 5, which represents filling in the neck region that stays unchanged or reduced, as shown with at least 2 consecutive control angiographies, at least 6 months apart, for not <1 year, or the remodeled appearance of a dilated and/or tortuous vessel in continuation with the parent artery without sac filling.


title: High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus.

text: UNLABELLED The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 as the causative agent of a severe respiratory disease with a fatality rate of approximately 30%. The high virulence and mortality rate prompted us to analyze aspects of MERS-CoV pathogenesis, especially its interaction with innate immune cells such as antigen-presenting cells (APCs). Particularly, we analyzed secretion of type I and type III interferons (IFNs) by APCs, i.e., B cells, macrophages, monocyte-derived/myeloid dendritic cells (MDDCs/mDCs), and by plasmacytoid dendritic cells (pDCs) of human and murine origin after inoculation with MERS-CoV. Production of large amounts of type I and III IFNs was induced exclusively in human pDCs, which were significantly higher than IFN induction by severe acute respiratory syndrome (SARS)-CoV. Of note, IFNs were secreted in the absence of productive replication. However, receptor binding, endosomal uptake, and probably signaling via Toll-like receptor 7 (TLR7) were critical for sensing of MERS-CoV by pDCs. Furthermore, active transcription of MERS-CoV N RNA and subsequent N protein expression were evident in infected pDCs, indicating abortive infection. Taken together, our results point toward dipeptidyl peptidase 4 (DPP4)-dependent endosomal uptake and subsequent infection of human pDCs by MERS-CoV. However, the replication cycle is stopped after early gene expression. In parallel, human pDCs are potent IFN-producing cells upon MERS-CoV infection. Knowledge of such IFN responses supports our understanding of MERS-CoV pathogenesis and is critical for the choice of treatment options. IMPORTANCE MERS-CoV causes a severe respiratory disease with high fatality rates in human patients. Recently, confirmed human cases have increased dramatically in both number and geographic distribution. Understanding the pathogenesis of this highly pathogenic CoV is crucial for developing successful treatment strategies. This study elucidates the interaction of MERS-CoV with APCs and pDCs, particularly the induction of type I and III IFN secretion. Human pDCs are the immune cell population sensing MERS-CoV but secrete significantly larger amounts of IFNs, especially IFN-α, than in response to SARS-CoV. A model for molecular virus-host interactions is presented outlining IFN induction in pDCs. The massive IFN secretion upon contact suggests a critical role of this mechanism for the high degree of immune activation observed during MERS-CoV infection.


Patient involvement in agenda setting for respiratory research in The Netherlands.


title: Increased risk of endemic mosquito-borne diseases in Canada due to climate change.

text: There are currently over 80 species of mosquito endemic in Canada-although only a few of these carry pathogens that can cause disease in humans. West Nile virus, Eastern equine encephalitis virus and the California serogroup viruses (including the Jamestown Canyon and snowshoe hare viruses) are mosquito-borne viruses that have been found to cause human infections in North America, including in Canada. Over the last 20 years, the incidence of most of these endemic mosquito-borne diseases (MBD) has increased approximately 10% in Canada, due in large part to climate change. It is anticipated that both the mosquito lifecycle and virus transmission patterns will be affected by climate change, resulting in an increase in both the range and local abundance of several important mosquito species. Laboratory studies and mathematical modelling suggest that increased ambient temperatures, changes in precipitation and extreme weather events associated with climate change will likely continue to drive mosquito vector and MBD range expansion, increasing the duration of transmission seasons and leading to MBD-related epidemics. Furthermore, Canada's endemic MBDs have complex transmission cycles, involving multiple reservoir hosts (birds and mammals), multiple pathogens and multiple mosquito species-all of which may be sensitive to climate and other environmental changes, and making forecasting of potential emerging trends difficult. These expected climate-induced changes in mosquitoes and MBDs underline the need for continued (and expanded) surveillance and research to ensure timely and accurate evaluation of the risks to the public health of Canadians.


The COVID-19 Pandemic Presents an Opportunity to Reassess the Value of Polysomnography.


title: Unexplained hyponatremia: seek and you will find.

text: BACKGROUND Hyponatremia is a common diagnostic challenge. METHODS An index case is presented to discuss the diagnostic approach to chronic and unexplained hyponatremia. RESULTS The index case concerns a 60-year-old man with chronic hepatitis C and previous alcohol use who was referred because of weight loss, poor dietary intake, dizzy spells, and unexplained hyponatremia (serum sodium 124-129 mmol/l). A low urine sodium concentration (20 mmol/l) and a low fractional sodium excretion (0.07%) were observed repeatedly, while urine osmolality was high (>400 mosm/kg). The central questions in this case are: what is the differential diagnosis, which tests are needed to confirm or exclude a diagnosis, and how would you proceed if no obvious cause is found? CONCLUSIONS The diagnosis of this case of unexplained hyponatremia was unexpected, but important because it was treatable. The challenges and caveats of the diagnostic approach to hyponatremia are discussed. A diagnostic algorithm to guide clinicians who are confronted with similar cases is presented.


title: Comparison of endoscopic closure modalities for standardized colonic perforations in a porcine colon model.

text: BACKGROUND AND STUDY AIM Colonic perforation is a serious complication of colonoscopy, with surgical repair usually indicated. The aim was to compare acute strength of various endoscopic colonic closure techniques by assessing air leak pressures in a previously described ex vivo experimental apparatus. METHODS Standardized colonic perforations were created using fresh porcine colon and subsequently closed on a bench. Six techniques included surgical suture (gold standard), QuickClips, T-tags, over-the-scope-clip (OTSC) system, and two types of flexible stapler (Covidien). After closure, each specimen was fixed in the apparatus and pressure was gradually increased until air bubbles were seen. Leak pressure was the primary outcome parameter. Closure using the gold standard (first 15 experiments) resulted in a mean leak pressure of 86.9 mmHg (SD 7). Using a noninferiority design a sample size of 12 specimens for each closure technique was determined. RESULTS Mean colotomy leak pressures in millimeters of mercury (mmHg) and difference (with 95% confidence intervals [CI]) between each technique and the gold standard were: QuickClips 85.1 (difference -1.8; 95% CI -7.0 to 3.9); T-tags 53.9 (difference -33.0; -39.0 to -27.0); OTSC 90.3 mmHg (difference 3.4; -6.1 to 12.9); 15-mm shaft stapler 98.5 mmHg (difference 9.7; 0.8 to 18.5) and 8-mm shaft stapler 96.6 mmHg (difference 11.6; 1.5 to 21.7). CONCLUSIONS OTSCs, QuickClips, and both flexible staplers produced results comparable to hand-sewn colotomy closure in this ex vivo porcine colonic model. These devices seem to be prime candidates for further evaluation in survival animal studies.


title: CXCL10 and trafficking of virus-specific T cells during coronavirus-induced demyelination.

text: Chronic expression of CXC chemokine ligand 10 (CXCL10) in the central nervous system (CNS) following infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) is associated with an immune-mediated demyelinating disease. Treatment of mice with anti-CXCL10 neutralizing antibody results in limited CD4+ T cell infiltration into the CNS accompanied by a reduction in white matter damage. The current study determines the antigen-specificity of the T lymphocytes present during chronic disease and evaluates how blocking CXCL10 signaling affects retention of virus-specific T cells within the CNS. CXCL10 neutralization selectively reduced accumulation and/or retention of virus-specific CD4+ T cells, yet exhibited limited effect on virus-specific CD8+ T cells. The response of CXCL10 neutralization on virus-specific T cell subsets is not due to differential expression of the CXCL10 receptor CXCR3 on T cells as there was no appreciable difference in receptor expression on virus-specific T cells during either acute or chronic disease. These findings emphasize the importance of virus-specific CD4+ T cells in amplifying demyelination in JHMV-infected mice. In addition, differential signals are required for trafficking and retention of virus-specific CD4+ and CD8+ T cells during chronic demyelination in JHMV-infected mice.


title: COUNTCOLORS, AN R PACKAGE FOR QUANTIFICATION OF THE FLUORESCENCE EMITTED BY PSEUDOGYMNOASCUS DESTRUCTANS LESIONS ON THE WING MEMBRANES OF HIBERNATING BATS.

text: Pseudogymnoascus destructans colonizes the wing membrane of hibernating bats with the potential to form dense fungal hyphae aggregates within cupping erosions. These fungal cupping erosions emit a characteristic fluorescent orange-yellow color when the wing membrane is transilluminated with 385 nm UV light. The purpose of this study was to create and validate the R package, countcolors, for quantifying the distinct orange-yellow ultraviolet (UV) fluorescence in bat-wing membrane lesions caused by P. destructans. Validation of countcolors was completed by first quantifying the percent area of 20, 2.5 cm2 images. These generated images were of two known pixel colors ranging from 0% to 100% of the pixels. The countcolors package accurately measured the known proportion of a given color in each image. Next, 40, 2.5 cm2 sections of UV transilluminated photographs of little brown bat (Myotis lucifugus) wings were given to a single evaluator. The area of fluorescence was both manually measured and calculated using image analysis software and quantified with countcolors. There was good agreement between the two methods (Pearson's correlation=0.915); however, the manual use of imaging software showed a consistent negative bias. Reproducibility of the analysis methods was tested by providing the same images to naive evaluators who previously never used the software; no significant difference (P=0.099) was found among evaluators. Using the R package countcolors takes less time than does manually measuring the fluorescence in image analysis software, and our results showed that countcolors can improve the accuracy when quantifying the area of P. destructans infection in bat wing-membranes.


title: TRIM56 is a virus- and interferon-inducible E3 ubiquitin ligase that restricts pestivirus infection.

text: The tripartite motif (TRIM) protein family comprises more than 60 members that have diverse functions in various biological processes. Although a small number of TRIM proteins have been shown to regulate innate immunity, much remains to be learned about the functions of the majority of the TRIM proteins. Here we identify TRIM56 as a cellular protein associated with the N-terminal protease (N(pro)) of bovine viral diarrhea virus (BVDV), a pestiviral interferon antagonist which degrades interferon regulatory factor 3 (IRF3) through the proteasome. We found that TRIM56 was constitutively expressed in most tissues, and its abundance was further upregulated moderately by interferon or virus. The manipulation of TRIM56 abundance did not affect the protein turnover of N(pro) and IRF3. Rather, ectopic expression of TRIM56 substantially impaired, while knockdown of TRIM56 expression greatly enhanced, BVDV replication in cell culture. The antiviral activity of TRIM56 depended on its E3 ubiquitin ligase activity as well as the integrity of its C-terminal region but was not attributed to a general augmentation of the interferon antiviral response. Overexpression of TRIM56 did not inhibit the replication of vesicular stomatitis virus or hepatitis C virus, a virus closely related to BVDV. Together, our data demonstrate that TRIM56 is a novel antiviral host factor that restricts pestivirus infection.


title: Well-Being During Coronavirus Disease 2019: A PICU Practical Perspective.

text: The importance of promoting well-being for healthcare professionals has never been as important as during the current coronavirus disease 2019 pandemic. It is recognized that the concept of well-being is a multifaceted phenomenon which is influenced by individual, team, and system characteristics. We outline an approach to practically initiating supportive strategies within the PICU using a well-being approach to improve baseline resilience alongside an acute rescue strategy utilizing a peer-support network. These strategies are practical interventions and we share them with the aim of encouraging the international PICU community to use these or other strategies to support their teams. We encourage shared learning and collaboration during these difficult times.


title: Toll-like receptor 8 senses degradation products of single-stranded RNA.

text: Toll-like receptor 8 (TLR8) recognizes viral or bacterial single-stranded RNA (ssRNA) and activates innate immune systems. TLR8 is activated by uridine- and guanosine-rich ssRNA as well as by certain synthetic chemicals; however, the molecular basis for ssRNA recognition has remained unknown. In this study, to elucidate the recognition mechanism of ssRNA, we determined the crystal structures of human TLR8 in complex with ssRNA. TLR8 recognized two degradation products of ssRNA—uridine and a short oligonucleotide—at two distinct sites: uridine bound the site on the dimerization interface where small chemical ligands are recognized, whereas short oligonucleotides bound a newly identified site on the concave surface of the TLR8 horseshoe structure. Site-directed mutagenesis revealed that both binding sites were essential for activation of TLR8 by ssRNA. These results demonstrate that TLR8 is a sensor for both uridine and a short oligonucleotide derived from RNA.


title: DNA damage effects of inhalation anesthetics in human bronchoalveolar cells.

text: BACKGROUND The main objective was to evaluate and compare the local genotoxicity of sevoflurane and desflurane in bronchoalveolar cells, while the secondary outcome was to detect systemic oxidative DNA damage. To our knowledge, our study is the first one to evaluate the local effects of inhalation anesthetics in human bronchoalveolar cells in patients. METHODS American Society of Anesthesiologists group I-II patients scheduled for lumbar discectomy surgery were enrolled in this randomized prospective study. Patients were randomized to sevoflurane or desflurane for anesthesia maintenance. Bronchoalveolar lavage samples and peripheral blood samples were taken at 2-time points: the first point (baseline, T1); and the second point (postexposure, T2). Final number of 48 samples were the sevoflurane (n = 22) and desflurane (n = 26) groups. Comet assay was applied to examine genotoxic properties. Oxidative DNA damage in plasma was measured with 8-hydroxy-2'-deoxyguanosine (8-OHdG). RESULTS T2 values were higher than baseline values in both the desflurane group (tail-length: 66 ± 24, %DNA in tail: 72 ± 60, tail moment: 47.52 ± 14.4; P = .001, P = .005, P = .001, respectively) and the sevoflurane group (tail-length: 58 ± 33, %DNA in tail: 88 ± 80, tail moment: 51.04 ± 26.4; P = .001, P = .012, P = .001, respectively). T2 plasma 8-OHdG levels were also higher than baseline levels in the desflurane group (3.91 ± 0.19 ng/ml vs 1.32 ± 0.20 ng/ml, P = .001) and sevoflurane group (3.98 ± 0.18 ng/ml vs 1.31 ± 0.11 ng/ml, P = .001). There were no differences between the 2 groups in comet parameters and 8-OHdG levels. CONCLUSION Our results indicate that both inhalation agents cause DNA damage in the bronchoalveolar cells. Also, we detected increases in plasma 8-OHdG concentrations. Local genotoxicity and systemic oxidized DNA damage were similar in both groups.


title: Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment.

text: Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.


Genealogy of Training in Vascular Neurosurgery.


Accelerating Development of SARS-CoV-2 Vaccines - The Role for Controlled Human Infection Models.


title: Pediatric Acute Lung Injury Epidemiology and Natural History study: Incidence and outcome of the acute respiratory distress syndrome in children.

text: OBJECTIVES The incidence and outcome of the acute respiratory distress syndrome in children are not well-known, especially under current ventilatory practices. The goal of this study was to determine the incidence, etiology, and outcome of acute respiratory distress syndrome in the pediatric population in the setting of lung protective ventilation. DESIGN A 1-yr, prospective, multicenter, observational study in 12 geographical areas of Spain (serving a population of 3.77 million ≤ 15 yrs of age) covered by 21 pediatric intensive care units. SUBJECTS All consecutive pediatric patients receiving invasive mechanical ventilation and meeting American-European Consensus Criteria for acute respiratory distress syndrome. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected. A total of 146 mechanically ventilated patients fulfilled the acute respiratory distress syndrome definition, representing a incidence of 3.9/100,000 population ≤ 15 yrs of age/yr. Pneumonia and sepsis were the most common causes of acute respiratory distress syndrome. At the time of meeting acute respiratory distress syndrome criteria, mean PaO2/FIO2 was 99 mm Hg ± 41 mm Hg, mean tidal volume was 7.6 mL/kg ± 1.8 mL/kg predicted body weight, mean plateau pressure was 27 cm H2O ± 6 cm H2O, and mean positive end-expiratory pressure was 8.9 cm ± 2.9 cm H2O. Overall pediatric intensive care unit and hospital mortality were 26% (95% confidence interval 19.6-33.7) and 27.4% (95% confidence interval 20.8-35.1), respectively. At 24 hrs, after the assessment of oxygenation under standard ventilatory settings, 118 (80.8%) patients continued to meet acute respiratory distress syndrome criteria (PaO2/FIO2 104 mm Hg ± 36 mm Hg; pediatric intensive care units mortality 30.5%), whereas 28 patients (19.2%) had a PaO2/FIO2 >200 mm Hg (pediatric intensive care units mortality 7.1%) (p = .014). CONCLUSIONS This is the largest study to estimate prospectively the pediatric population-based acute respiratory distress syndrome incidence and the first incidence study performed during the routine application of lung protective ventilation in children. Our findings support a lower acute respiratory distress syndrome incidence and mortality than those reported for adults. PaO2/FIO2 ratios at acute respiratory distress syndrome onset and at 24 hrs after onset were helpful in defining groups at greater risk of dying (clinical trials registered with http://www.clinicaltrials.gov; NCT 01142544).


title: [CoViD-19 and chronic diseases: current knowledge, future steps and the MaCroScopio project.]

text: Chronicity and comorbidity influence the risk of CoViD-19 infection and the course of the disease. Epidemiological data and studies performed show different rates of chronic diseases and multimorbidity among patients affected by CoViD-19 in the various countries and areas, but they consistently stress their impact on CoViD-19 infection. In order to protect chronic and frail patients, the Italian Medicines Agency has taken measures to extend the therapeutic plans and monitoring registers; hopefully, therapeutic plans for antidiabetics, drugs for respiratory diseases and oral anticoagulant drugs will be abolished since they do not offer any additional advantage in terms of appropriateness and traceability of outcomes. The MaCroScopio project (Observatory on Chronic Diseases), regarding the CoViD-19 emergency, has started a new research path to foster the integration of the administrative data flows with the CoViD-19 Registers for planning and research purposes in the context of chronicity, as well as to evaluate the economic and organizational impact of the pandemic.


title: Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

text: BACKGROUND Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).


Physical Distancing and Emotional Closeness Amidst COVID-19.


title: Predictors of multidisciplinary rehabilitation outcomes in patients with chronic musculoskeletal pain: protocol for a systematic review and meta-analysis.

text: BACKGROUND Chronic musculoskeletal pain is a major public health problem. Early prediction for optimal treatment results has received growing attention, but there is presently a lack of evidence regarding what information such proactive management should be based on. This study protocol, therefore, presents our planned systematic review and meta-analysis on important predictive factors for health and work-related outcomes following multidisciplinary rehabilitation (MDR) in patients with chronic musculoskeletal pain. METHODS We aim to perform a synthesis of the available evidence together with a meta-analysis of published peer-reviewed original research that includes predictive factors preceding MDR. Included are prospective studies of adults with benign, chronic (> 3 months) musculoskeletal pain diagnoses who have taken part in MDR. In the studies, associations between personal and rehabilitation-based factors and the outcomes of interest are reported. Outcome domains are pain, physical functioning including health-related quality of life, and work ability with follow-ups of 6 months or more. We will use a broad, explorative approach to any presented predictive factors (demographic, symptoms-related, physical, psychosocial, work-related, and MDR-related) and these will be analyzed through (a) narrative synthesis for each outcome domain and (b) if sufficient studies are available, a quantitative synthesis in which variance-weighted pooled proportions will be computed using a random effects model for each outcome domain. The strength of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation. DISCUSSION The strength of this systematic review is that it aims for a meta-analysis of prospective cohort or randomized controlled studies by performing an extensive search of multiple databases, using an explorative study approach to predictive factors, rather than building on single predictor impact on the outcome or on predefined hypotheses. In this way, an overview of factors central to MDR outcome can be made and will help strengthen the evidence base and inform a wide readership including health care practitioners and policymakers. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42016025339.


title: Age- and Sex-Specific Risk Profiles and In-Hospital Mortality in 13,932 Spanish Stroke Patients.

text: BACKGROUND In-hospital stroke death rate is an important sanitary issue. Despite advances in the acute phase management of stroke patients, mortality and disability rates remain high. In aging populations and with different mortality between the sexes in general, the study of sex- and age-related differences becomes increasingly relevant for optimization of post-acute clinical care of stroke patients. METHODS We designed a cohort follow-up study with 13,932 consecutive ischemic stroke (IS) patients from 19 Spanish hospitals. Data was obtained from the Spanish Stroke Registry; transient ischemic attacks and ages <18 years were excluded. Patients were organised by age group and sex. We compared female and male patient cohorts within and across age groups univariately and used multivariable logistic regression to adjust for confounders in differential in-hospital mortality. RESULTS The median (percentiles 2.5 and 97.5%) age was 78 (41-92) years old for women and 71 (41-92) for men. IS women were more likely to be older, to exhibit cardio-embolic aetiology, and less likely to have been admitted to a stroke unit or to have had a stroke code activated. Both pre-stroke modified Rankin Scale and National Institute of Health Stroke Scale (NIHSS) scores at admission increased significantly with age and were higher in women than those in men. Differences in distributions of common risk factors for IS and of in-hospital outcomes between women and men actually changed with patient's age. It is to be noted here that although there were no statistically significant differences (p > 0.05) between the sexes within any age group, in-hospital mortality appeared significantly higher in women than that in men when analysed overall, due to confounding. Death was more closely related to stroke in women than in men and occurred earlier. Although there were some age-specific sex differences between the predictors for in-hospital mortality, stroke severity measured by NIHSS was the main predictor of in-hospital mortality for both sexes. Topographic classifications - partial anterior circulatory infarct and total anterior circulatory infarct - were significant prognostic factors for men aged <60 years and for those in the 60-69 years range respectively. CONCLUSION Although most of our findings were consistent with previous studies, it is important to take into account and highlight differences in in-hospital mortality between the sex and age group. Not to account for age-related differences between the sexes can give false results that may mislead management decisions. As most deaths in women were related to stroke, it is important to improve their early management, stroke code activation, access to stroke units and/or revascularisation therapies, especially in the older age groups.