title: Aromatic amino acids in the juxtamembrane domain of severe acute respiratory syndrome coronavirus spike glycoprotein are important for receptor-dependent virus entry and cell-cell fusion.

text: The severe acute respiratory syndrome coronavirus (SARS-CoV) spike glycoprotein (S) is a class I viral fusion protein that binds to its receptor glycoprotein, human angiotensin converting enzyme 2 (hACE2), and mediates virus entry and cell-cell fusion. The juxtamembrane domain (JMD) of S is an aromatic amino acid-rich region proximal to the transmembrane domain that is highly conserved in all coronaviruses. Alanine substitutions for one or two of the six aromatic residues in the JMD did not alter the surface expression of the SARS-CoV S proteins with a deletion of the C-terminal 19 amino acids (S Delta19) or reduce binding to soluble human ACE2 (hACE2). However, hACE2-dependent entry of trypsin-treated retrovirus pseudotyped viruses expressing JMD mutant S Delta19 proteins was greatly reduced. Single alanine substitutions for aromatic residues reduced entry to 10 to 60% of the wild-type level. The greatest reduction was caused by residues nearest the transmembrane domain. Four double alanine substitutions reduced entry to 5 to 10% of the wild-type level. Rapid hACE2-dependent S-mediated cell-cell fusion was reduced to 60 to 70% of the wild-type level for all single alanine substitutions and the Y1188A/Y1191A protein. S Delta19 proteins with other double alanine substitutions reduced cell-cell fusion further, from 40% to less than 20% of wild-type levels. The aromatic amino acids in the JMD of the SARS-CoV S glycoprotein play critical roles in receptor-dependent virus-cell and cell-cell fusion. Because the JMD is so highly conserved in all coronavirus S proteins, it is a potential target for development of drugs that may inhibit virus entry and/or cell-cell fusion mediated by S proteins of all coronaviruses.


Covid-19 and ethnic minorities: an urgent agenda for overdue action.


title: Stress urinary incontinence and LUTS in women--effects on sexual function.

text: The sexual impact of urinary incontinence in women depends on a host of parameters, including physical, psychological, social and cultural dimensions. Evaluation of the effects of stress urinary incontinence (SUI) and lower urinary tract symptoms on sexual function is often biased by their common association with other pelvic floor disorders, such as pelvic organ prolapse, which also affect sexual satisfaction. Indeed, these complexities are reflected in the literature, which shows considerable disparity in sexual functional characteristics in women with incontinence both before and after treatment. This discordance is further emphasized by heterogeneity in study design, quality and analysis. Here, we describe the nature of sexual dysfunction in women with incontinence, including coital incontinence. The various treatments for SUI, which include transvaginal tape surgeries, can also affect sexual function, positively or negatively. Coital incontinence seems to be a good predictor of an improvement in postoperative sexual parameters: its cure, achieved by >90% of women, to a large extent explains the sexual benefits reported in several studies. By contrast, deterioration in sexual function is sometimes reported after surgery, with de novo or worsened dyspareunia being the most common cause. The literature does not contain any convincing arguments for one treatment or another on the basis of sexual functional outcome.


title: Role of robotic surgery in urogynecologic surgery and radical hysterectomy: how far can we go?

text: PURPOSE OF REVIEW The purpose is to review the current literature regarding robotic assistance in urogynecologic surgery and radical pelvic surgery and to discuss the future of robotics in these two areas of gynecology. RECENT FINDINGS When the first and only Food and Drug Administration-approved robot-assisted device, the daVinci surgical system, was approved for use in gynecology in April 2005, many procedures were translated to a robotic approach. In the field of urogynecology, much attention was given to the use of robotic assistance for sacrocolpopexy. In oncology, there was an attraction to the use of robotics for radical hysterectomies. There are a number of published observational studies comparing the outcomes of both robot-assisted laparoscopic sacrocolpopexy (RALS) and robot-assisted radical hysterectomy (RRH) to their conventional laparoscopic and open versions. Overall, the literature suggests that the use of robotics for these procedures increases operative time and cost, but decreases estimated blood loss and length of stay. The complication rates appear to be similar. Recurrence of apical prolapse after RALS appears to be similar to that in conventional laparoscopic or open sacrocolpopexy. The number of lymph nodes harvested is the same or increases with RRH, whereas the disease-free progression and overall survival are similar for all the methods of radical hysterectomy. SUMMARY Literature suggests that RALS and RRH have equivalent outcomes when compared to conventional laparoscopic and open techniques. The question is whether the use of robotics that combines the outcomes of an open procedure, the benefits of minimally invasive surgery, and easy adoptability will outweigh the increased cost and time associated with robotic surgery.


title: Gender-related long-term outcome of primary femoropopliteal stent placement for peripheral artery disease.

text: PURPOSE To evaluate gender-related long-term outcomes in patients undergoing stent treatment of femoropopliteal peripheral artery disease. METHODS Between September 2006 and August 2010, all 517 patients (333 men and 184 women; mean age 70.6 years) undergoing primary stent placement in femoropopliteal atherosclerotic lesions at 2 European vascular centers were prospectively enrolled in the study. The main study outcome was primary stent patency. Secondary outcomes included secondary patency, limb salvage, and all-cause mortality. RESULTS Women had a higher incidence of critical limb ischemia (32.1% vs. 16.9%, p<0.001). Lesion characteristics according to the TransAtlantic Inter-Society Consensus (TASC) classification were comparable in both genders (p=0.52), although total occlusions and popliteal involvement were observed more frequently in female patients (p=0.043 and p=0.001, respectively). Both genders showed similar 5-year primary patency rates (64.3% men vs. 58.1% women, p=0.11). A statistically significant difference was observed concerning the secondary patency rates in favor of men (71.9% vs. 66.8% at 5 years, p=0.005). Limb salvage rates did not vary between the groups (p=0.83). Survival rates were comparable at 5 years (83.3% and 82.6% for men and women, respectively; p=0.63), although female patients were older at their presentation (68.5 vs. 74.3 years, p<0.001). Female gender was an independent risk factor for restenosis for TASC C/D lesions (primary patency rate 39.8% in women vs. 62.0% in men; p=0.002). Finally, critical limb ischemia was an independent risk factor for restenosis in women (odds ratio 1.5). CONCLUSION Female gender was associated with a higher prevalence of critical limb ischemia, poorer secondary patency, and more frequent restenosis in TASC C/D lesions. Endovascular treatment of femoropopliteal lesions provides equal results between genders in terms of primary stent patency in the long term.


title: Vertical Midface Lifting with Periorbital Anchoring in the Management of Lower Eyelid Retraction: A 10-Year Clinical Retrospective Study.

text: BACKGROUND Lower eyelid retraction can be the unfortunate result of aesthetic surgery, trauma, disease, or the aging processes. The purpose of this article is to assess whether midface lifting based on purely vertical repositioning constitutes an effective procedure for its correction. METHODS A retrospective study was carried out on 199 patients (311 eyelids) operated on between January of 2004 and January of 2014. The various causes of eyelid retraction in this population included cosmetic blepharoplasty (56.8 percent), involutional ectropion (23.1 percent), tumor resection (9.5 percent), facial nerve paralysis (8.5 percent), and trauma and related surgery (2 percent). The study was restricted exclusively to cases of moderate and severe lower eyelid retraction addressed by means of midface lifting. The mean follow-up time was 16.8 months. All of the patients were subjected to midface lifting with strengthening of the lateral canthus. A spacer graft was also used in 37.7 percent of the cases. RESULTS One hundred ninety-five patients (97.9 percent) displayed objective improvement of the eyelid retraction and a marked degree of improvement both in aesthetic terms and as regards the functional disorders reported. Only four patients (2 percent) presented complications such as needing another operation. CONCLUSION Midface lifting based on purely vertical repositioning makes it possible to recruit a considerable amount of "new" skin at the lower eyelid, thus ensuring a decrease in vertical distraction and correct recovery of the height of the external lamellar plane. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, IV.


title: Acute-phase response following full-mouth versus quadrant non-surgical periodontal treatment: A randomized clinical trial.

text: AIM A moderate acute-phase response occurs 24-h following full-mouth non-surgical treatment (FM-SRP). The aim of this study was to compare acute-phase (24-h) and medium-term (3 months) inflammation after quadrant scaling (Q-SRP) versus FM-SRP. MATERIAL & METHODS Thirty-eight periodontitis-affected subjects were randomly allocated to FM-SRP or Q-SRP after a baseline visit. Periodontal and anthropometric parameters were collected at baseline and 3 months. Serum samples were drawn at baseline, 1, 7, and 90 days after treatment. High-sensitivity assays of inflammation and endothelial assays were performed. RESULTS FM-SRP produced a greater acute-phase response after 24 h [threefold increase in C-reactive protein (CRP), twofold increase in interleukin (IL-6), and a slight increase in tumour necrosis factor]. No differences in systemic biomarkers were noted between groups at any later follow-ups. Both periodontal treatments produced a comparable improvement in clinical periodontal parameters with no between-group differences. Treatment time was positively associated with the relative 24-h increase in CRP (R = 0.5, p < 0.001) and IL-6 (R = 0.5, p = 0.002), while the number of deeper (>6 mm) pockets predicted only the relative increase in IL-6 (R = 0.4, p < 0.05). CONCLUSIONS FM-SRP triggers a moderate acute-phase response of 24 h duration compared to Q-SRP. Further research is needed to assess the eventual impact of such findings on the risk of vascular events is advocated. (ClinicalTrials.gov NCT01857804).


title: Corking the WEB and coiling through a jailed microcatheter: WEB assisted coiling, a useful technique avoiding the use of stents in treating wide-necked large intracranial aneurysms.

text: The WEB is an endovascular flow-disrupting device used in treating wide-necked intracranial aneurysms. Although the device is available in varying sizes, large aneurysms pose a challenge with the need for custom-made devices. We describe the use of coils as an adjunct to the WEB device in successfully treating large aneurysms in two patients, one with an acutely ruptured aneurysm. This novel technique of jailing a microcatheter, deploying the WEB and then coiling the aneurysm saves the need for intracranial stenting, thereby avoiding the need for antiplatelet therapy, which is of benefit in the setting of acute aneurysm rupture.


title: Laparoscopic sleeve gastrectomy using a synthetic bioabsorbable staple line reinforcement material: Post-operative complications and 6 year outcomes.

text: BACKGROUND Gastric leak after laparoscopic sleeve gastrectomy (LSG) is a serious complication. Currently, the literature lacks long-term outcomes in LSG and leak rates after reinforcement of the staple line. The aims are two-fold: to present leak rates from using staple line reinforcement and six year outcomes of LSG in relation to resolution of obesity-related comorbidities and long-term weight loss. MATERIALS AND METHODS This is a single-institution, retrospectively reviewed study of 204 patient case files. Data from all patients undergoing LSG between December 2007 and May 2013 was collected. RESULTS The total complication rate was 6.9% (14/204), with no recorded staple line leaks. The mean postoperative Body Mass Index (BMI) at 1 year, 2 years, 3 years, 4 years, 5 years, and 6 years was 39.3 ± 8, 38.7 ± 8, 40.4 ± 9, 40.5 ± 10, 43.0 ± 10, and 42.4 ± 7, respectively. The mean % excess weight loss at 1 year, 3 years, and 6 years was 48.4 ± 19, 51.7 ± 28, and 41.0 ± 21, respectively. There were no significant differences between follow-ups at year 1 and 3 (p > 0.05), and between year 3 and 6 (p > 0.05) for the mean % excess weight loss. The resolution rates for all patients were 74%, 61%, 79%, and 90% for hypertension, hypercholesterolemia, diabetes mellitus type 2 and obstructive sleep apnea, respectively. CONCLUSION The synthetic bioabsorbable reinforcement material shows no staple line leaks making it safe to use. LSG as a procedure had a high resolution of obesity-related comorbidities as well as sustainable long-term weight loss.


title: Preoperative embolization of intracranial hemangiopericytomas: case series and introduction of the transtumoral embolization technique.

text: BACKGROUND AND PURPOSE Hemangiopericytomas (HPCs) are rare dural-based neoplasms. Preoperative embolization of these notoriously hypervascular tumors can be challenging as they often receive their dominant blood supply from pial feeders arising from the internal carotid artery (ICA) or vertebrobasilar (VB) circulation. This study reviews our historical experience with HPC embolization and introduces the transtumoral technique for backfilling pial tumor vasculature by delivering Onyx-18 through diminutive external carotid artery (ECA) feeders. METHODS A retrospective review of all preoperative HPC embolizations performed at Anonymous University #1 (September 2002-November 2014) and Anonymous University #2 (January 2014-November 2014) is presented. RESULTS Fifteen patients with pathologically confirmed HPC underwent 17 embolizations. More extensive devascularization percentages were achieved for HPCs with primarily ECA blood supply (76.4±10.7%; n=6) than with HPCs supplied via the ICA/VB circulation (57.9±26.9%; n=8; p=0.046). There was a trend towards greater devascularization of ICA/VB-dominant HPCs embolized with Onyx (70.0±34.6%; n=4) versus polyvinyl alcohol particles (33.3±15.3%; n=3). The extent of angiographic devascularization negatively correlated with intraoperative blood loss (rho=-0.71; p=0.005). There were no embolization-related complications. CONCLUSIONS The extent of preoperative embolization of HPCs correlates with decreased intraoperative blood loss. However, HPCs with an ICA/VB-dominant blood supply remain challenging embolization targets, demonstrating reduced devascularization percentages compared with ECA-dominant counterparts. The authors favor the use of Onyx for ICA/VB-dominant HPCs, noting a trend towards an improved devascularization rate.


Covid-19: Questions remain over UK government's PPE guidance.


Increased CSF levels of IL-1β, IL-6, and ACE in SARS-CoV-2-associated encephalitis.


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title: Integrating biophysics with HTS-driven drug discovery projects.

text: Over the past decade biophysics has become an established discipline in HTS hit triaging, owing to its high fidelity in detecting protein-ligand interactions. Many pharma companies are using biophysical techniques to filter HTS output for false positives, as will be discussed in this review. Moreover, I will demonstrate how the earlier application of biophysics, already at the HTS assay development stage, is potentially even more impactful. Two key areas here are early mode-of-action studies and ensuring that the HTS assay and subsequent cascade are fit for purpose. Top-level results from 20 in-house projects are shown to underpin the impact of these studies.


title: Humidification performance of heat and moisture exchangers for pediatric use.

text: Background. While heat and moisture exchangers (HMEs) have been increasingly used for humidification during mechanical ventilation, the efficacy of pediatric HMEs has not yet been fully evaluated. Methods. We tested ten pediatric HMEs when mechanically ventilating a model lung at respiratory rates of 20 and 30 breaths/min and pressure control of 10, 15, and 20 cmH(2)O. The expiratory gas passed through a heated humidifier. We created two rates of leakage: 3.2 L/min (small) and 5.1 L/min (large) when pressure was 10 cmH(2)O. We measured absolute humidity (AH) at the Y-piece. Results. Without leakage, eight of ten HMEs maintained AH at more than 30 mg/L. With the small leak, AH decreased below 30 mg/L (26.6 to 29.5 mg/L), decreasing further (19.7 to 27.3 mg/L) with the large leak. Respiratory rate and pressure control level did not affect AH values. Conclusions. Pediatric HMEs provide adequate humidification performance when leakage is absent.


title: Respiratory Outbreak Investigations: How Many Specimens Should Be Tested?

text: To determine the optimal number of specimens for virus detection in a respiratory outbreak, laboratory results from 2 Canadian public health laboratories were reviewed. The evidence suggests that 3 specimens are sufficient for detection of a virus in >95% of outbreaks, thereby reducing laboratory costs.


title: A Virtual Comparison of the eCLIPs Device and Conventional Flow-Diverters as Treatment for Cerebral Bifurcation Aneurysms.

text: PURPOSE Effective, consistent, and complication-free treatment of cerebral bifurcation aneurysms remains elusive despite a pressing need, with the majority of lesions presenting in such locations. Current treatment options focus either on aneurysm coil retention, supported by a stent-like device positioned in the parent vessel lumen, or intrasaccular devices that disrupt flow within the aneurysm dome. A third alternative, i.e., the use of conventional (intraluminal) flow-diverters to treat such bifurcation aneurysms raises the problem that at least one daughter vessel needs to be jailed in such a deployment. The eCLIPs is a stent-like device that offers the possibility of flow-diversion at the aneurysm neck, without the drawbacks of daughter vessel occlusion or those of intrasaccular deployment. METHODS In this study the eCLIPs device was virtually deployed in five cerebral bifurcation aneurysms and compared with a conventional tubular flow-diverter device. Computational fluid dynamics (CFD) simulations of the aneurysm haemodynamic environment pre- and post-implantation were conducted, and focussed on metrics associated with successful aneurysm occlusion. Absolute and relative reductions in aneurysm inflow rate (Q) and time-averaged wall shear stress (TAWSS) were recorded. RESULTS The eCLIPs device was found to perform in a similar qualitative fashion to tubular flow-diverters, with overall reduction of metrics being somewhat more modest however, when compared to such devices. Aneurysm inflow reduction and TAWSS reduction were typically 10-20% lower for the eCLIPs, when compared to a generic flow diverter (FDBRAIDED) similar to devices currently in clinical use. The eCLIPs was less effective at diffusing inflow jets and at reducing the overall velocity of the flow, when compared to these devices. This result is likely due to the larger device pore size in the eCLIPs. Notably, it was found that the eCLIPs provided approximately equal resistance to flow entering and exiting the aneurysm, which was not true for the FDBRAIDED device, where high-speed concentrations of outflow were seen at the aneurysm neck along with local TAWSS elevation. The clinical implications of such behaviour are not examined in detail here but could be significant. CONCLUSIONS Our findings indicate that the eCLIPs device acts as a flow-diverter for bifurcation aneurysms, with somewhat diminished occlusion properties comparing to tubular flow diverters but without the jailing and diminished flow evident in a daughter vessel associated with use of conventional devices.


In considerations of robotic colorectal surgery within a COVID-19 pandemic.


Mission control on Skype: how to fly a spacecraft during a pandemic.


COVID-19 and lockdown: living in 'interesting times'.


title: Genetic progression of Barrett's oesophagus to oesophageal adenocarcinoma.

text: Barrett's oesophagus (BE) is the premalignant condition associated with the development of oesophageal adenocarcinoma (OAC). Diagnostically, p53 immunohistochemistry remains the only biomarker recommended clinically to aid histopathological diagnosis. The emerging mutational profile of BE is one of highly heterogeneous lesions at the genomic level with many mutations already occurring in non-dysplastic tissue. As well as point mutations, larger scale copy-number changes appear to have a key role in the progression to OAC and clinically applicable assays for the reliable detection of aneuploidy will be important to incorporate into future clinical management of patients. For some patients, the transition to malignancy may occur rapidly through a genome-doubling event or chromosomal catastrophe, termed chromothripsis, and detecting these patients may prove especially difficult. Given the heterogeneous nature of this disease, sampling methods to overcome inherent bias from endoscopic biopsies coupled with the development of more objective biomarkers than the current reliance on histopathology will be required for risk stratification. The aim of this approach will be to spare low-risk patients unnecessary procedures, as well as to provide endoscopic therapy to the patients at highest risk, thereby avoiding the burden of incurable metastatic disease.


title: Electronic versus traditional chest tube drainage following lobectomy: a randomized trial.

text: OBJECTIVES Electronic drainage systems have shown superiority compared with traditional (water seal) drainage systems following lung resections, but the number of studies is limited. As part of a medico-technical evaluation, before change of practice to electronic drainage systems for routine thoracic surgery, we conducted a randomized controlled trial (RCT) investigating chest tube duration and length of hospitalization. METHODS Patients undergoing lobectomy were included in a prospective open label RCT. A strict algorithm was designed for early chest tube removal, and this decision was delegated to staff nurses. Data were analysed by Cox proportional hazard regression model adjusting for lung function, gender, age, BMI, video-assisted thoracic surgery (VATS) or open surgery and presence of incomplete fissure or pleural adhesions. Time was distinguished as possible (optimal) and actual time for chest tube removal, as well as length of hospitalization. RESULTS A total of 105 patients were randomized. We found no significant difference between the electronic group and traditional group in optimal chest tube duration (HR = 0.83; 95% CI: 0.55-1.25; P = 0.367), actual chest tube duration (HR = 0.84; 95% CI: 0.55-1.26; P = 0.397) or length of hospital stay (HR = 0.91; 95% CI: 0.59-1.39; P = 0.651). No chest tubes had to be reinserted. Presence of pleural adhesions or an incomplete fissure was a significant predictor of chest tube duration (HR = 1.72; 95% CI: 1.15-2.77; P = 0.014). CONCLUSIONS Electronic drainage systems did not reduce chest tube duration or length of hospitalization significantly compared with traditional water seal drainage when a strict algorithm for chest tube removal was used. This algorithm allowed delegation of chest tube removal to staff nurses, and in some patients chest tubes could be removed safely on the day of surgery.


title: Impact of irbesartan, an angiotensin receptor blocker, on uric acid level and oxidative stress in high-risk hypertension patients.

text: Hyperuricemia is a known cardiovascular risk factor. The angiotensin II receptor blocker (ARB) losartan is known to decrease serum uric acid (UA) level. A recent in vitro study demonstrated a strong interaction between irbesartan and UA transporters that exceeded that of losartan. The purpose of the present study was to evaluate the hypouricemic effect of irbesartan in a clinical setting. A total of 40 high-risk hypertensive outpatients with coronary artery disease, cerebrovascular disease and/or diabetes complications who were taking ARBs other than irbesartan and losartan were enrolled in this study. After a 4-week control period, the patients' prescribed ARBs were exchanged for an equivalent dose of irbesartan. We assessed blood pressure, heart rate, serum UA level, parameters of lipid and glucose metabolism, cardiac and renal function and inflammatory and oxidative stress markers in blood samples taken immediately before the initiation of irbesartan treatment and again after 12 weeks of treatment. All 40 recruited patients were followed (31 men and 9 women, mean age: 68 years) without any dropouts. During the 12 weeks of irbesartan treatment, no significant changes in blood pressure, heart rate, parameters of lipid or glucose metabolism or other biomarkers of cardiac function, renal function, or inflammation were observed. However, UA level (5.9±1.6 to 5.5±1.6 mg ml(-1), P=0.028) and the oxidative stress marker derivative reactive oxygen metabolites (dROMs) (354±83 to 310±65 U.CARR, P<0.001) were significantly lower at 12 weeks of treatment compared with before treatment. These results suggest that irbesartan has beneficial effects on hyperuricemia and oxidative stress.


title: Designing liver resections and pushing the envelope with resections for hepatic colorectal metastases.

text: Current concepts in the management of hepatic metastases have changed dramatically over the past two decades. Multidisciplinary therapies including chemotherapy, surgery, and regional therapy have alone and in combination significantly improved the survival of patients with metastatic colorectal cancer. Conditions that were previously considered hopeless and treated merely for palliation can now be approached with curative intent. In this paper, we review the surgical treatment for colorectal cancer liver metastasis (CRLM) and describe a paradigm-shift in the management of complex heretofore-considered unresectable CRLM. Utilizing advanced multidisciplinary treatment strategies has improved the prognosis of patients with stage IV colorectal cancer to the point where we may question whether CRLM are now a chronic disease.


title: Lumbar spinal epidural arteriovenous fistula with perimedullary venous drainage after endoscopic lumbar surgery.

text: Spinal epidural arteriovenous fistulas (AVFs) with perimedullary venous drainage are rare. This report describes a case of lumbar epidural AVF in a patient with a history of endoscopic lumbar discectomy at the same level 8 years prior to presenting with progressive myelopathy secondary to retrograde venous reflux into the perimedullary vein. A 69-year-old man presented with progressive lower extremity weakness and sensory disturbance and loss of sphincter control 8 years after endoscopic lumbar discectomy for a disc herniation at L4-5 level. Magnetic resonance imaging showed spinal cord edema and dilated intradural perimedullary vessels. Spinal angiography revealed an epidural AVF at the site of the previous endoscopic lumbar surgery with intradural perimedullary venous drainage. The fistula was successfully occluded via endovascular transarterial embolization, and the patient had stabilization of his neurological deficits. Lumbar spinal epidural AVFs, especially those associated with iatrogenic trauma, are rare. Endoscopic surgical procedure can occlude the epidural venous plexus and disturb venous drainage, thereby inducing local venous hypertension and leading to epidural AVF with perimedullary venous drainage. This type of pathology should be considered within the differential diagnosis of delayed neurological deterioration after spinal surgery.


title: Associations of Ischemic Lesion Volume With Functional Outcome in Patients With Acute Ischemic Stroke: 24-Hour Versus 1-Week Imaging.

text: BACKGROUND AND PURPOSE Ischemic lesion volume (ILV) on noncontrast computed tomography at 1 week can be used as a secondary outcome measure in patients with acute ischemic stroke. Twenty-four-hour ILV on noncontrast computed tomography has greater availability and potentially allows earlier estimation of functional outcome. We aimed to assess lesion growth 24 hours after stroke onset and compare the associations of 24-hour and 1-week ILV with functional outcome. METHODS We included 228 patients from MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), who received noncontrast computed tomography at 24-hour and 1-week follow-up on which ILV was measured. Relative and absolute lesion growth was determined. Logistic regression models were constructed either including the 24-hour or including the 1-week ILV. Ordinal and dichotomous (0-2 and 3-6) modified Rankin scale scores were, respectively, used as primary and secondary outcome measures. RESULTS Median ILV was 42 mL (interquartile range, 21-95 mL) and 64 mL (interquartile range: 30-120 mL) at 24 hours and 1 week, respectively. Relative lesion growth exceeding 30% occurred in 121 patients (53%) and absolute lesion growth exceeding 20 mL occurred in 83 patients (36%). Both the 24-hour and 1-week ILVs were similarly significantly associated with functional outcome (both P<0.001). In the logistic analyses, the areas under the curve of the receiver-operator characteristic curves were similar: 0.85 (95% confidence interval, 0.80-0.90) and 0.87 (95% confidence interval, 0.82-0.91) for including the 24-hour and 1-week ILV, respectively. CONCLUSIONS Growth of ILV is common 24-hour poststroke onset. Nevertheless, the 24-hour ILV proved to be a valuable secondary outcome measure as it is equally strongly associated with functional outcome as the 1-week ILV. CLINICAL TRIAL REGISTRATION URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758.


Triage of functional, female and neuro-urology patients during and immediately after the Covid-19 outbreak.


title: Is the Pace of Biomedical Innovation Slowing?

text: The pace of biomedical innovation is important because it determines the rate of progress in medicine and allied disciplines. A review of the history of medical advances reveals that the three decades from 1950 to 1980 were a particularly innovative time. Subsequent decades have seen fewer seminal advances, despite continued improvements in many biomedical technologies. Although the biomedical sciences continue to be innovative, the question posed in this essay is whether the rate of innovation has slowed relative to the available knowledge base. The pace of innovation varies tremendously depending on the specific field considered. Overall, the pace of innovation may be slower than in the past, especially when measured against the biomedical knowledge base available today versus that available then. Ten factors are discussed that could be slowing biomedical innovation. If biomedical innovation is slowing, then restoring a faster pace would require the cooperation of government, industry and academia, for the problems are multifaceted and intertwined.


title: Temperature-sensitive mutants and revertants in the coronavirus nonstructural protein 5 protease (3CLpro) define residues involved in long-distance communication and regulation of protease activity.

text: Positive-strand RNA virus genomes are translated into polyproteins that are processed by viral proteases to yield functional intermediate and mature proteins. Coronaviruses (CoVs) carry genes that encode an nsp5 protease (also known as 3CLpro or Mpro) responsible for 11 maturation cleavages. The nsp5 structure contains two chymotrypsin-like domains (D1 and D2) and a unique domain (D3), and forms functional dimers. However, little is known of interactions or communication across the structure of the protease during nsp5 activity. Using reverse genetic mutagenesis of the CoV murine hepatitis virus (MHV) nsp5, we identified a new temperature-sensitive (ts) mutation in D2 of nsp5 (Ser133Ala) and confirmed a ts residue in D3 (Phe219Leu). Both D2-tsS133A and D3-tsF219L were impaired for viral replication and nsp5-mediated polyprotein processing at the nonpermissive temperature. Passage of tsS133A and tsF219L at the nonpermissive temperature resulted in emergence of multiple second-site suppressor mutations, singly and in combinations. Among the second-site mutations, a D2 His134Tyr change suppressed the ts phenotype of D2-tsS133A and D3-tsF219L, as well as the previously reported D2-tsV148A. Analysis of multiple CoV nsp5 structures, and alignment of nonredundant nsp5 primary sequences, demonstrated that ts and suppressor residues are not conserved across CoVs and are physically distant (>10 Å) from each other, from catalytic and substrate-binding residues, and from the nsp5 dimer interface. These findings demonstrate that long-distance communication pathways between multiple residues and domains of nsp5 play a significant role in nsp5 activity and viral replication, suggesting possible novel targets for non-active site inhibitors of nsp5.


title: The efficacy and safety of preoperative lumbar drain placement in anterior skull base surgery.

text: This study assesses the efficacy of preoperative lumbar drain (LD) placement prior to elective open cranial and endoscopic anterior skull base (ASB) surgery in reducing postoperative cerebrospinal fluid (CSF) leak. A retrospective review of 93 patients who underwent LD placement at our institution between 2006 and 2011 was performed. Of these patients, 43 underwent elective LD placement prior to ASB surgery; 2 patients had evidence of CSF rhinorrhea prior to surgery, and 41 had no evidence of a preoperative CSF leak. Of those 41 patients, 2 developed CSF rhinorrhea (2/41= 4.9%) as a result of surgery-all in our endoscopic patient population (N = 21; 2/21= 9.5%). No postoperative CSF leaks were noted in our open ASB surgery cohort (N = 20). Other complications were rare, but we encountered two instances of delayed malignant cerebral edema in the open ASB cohort that are discussed in detail. Overall, preoperative LD placement was found to be an effective means of preventing postoperative CSF leaks after ASB approaches, but potential and significant intracranial complications may occur in select patients that merit careful consideration prior to LD placement.


title: Respective impact of lowering body temperature and heart rate on mortality in septic shock: mediation analysis of a randomized trial.

text: PURPOSE We previously showed that external cooling decreases day 14 mortality in febrile septic shock. Because cooling may participate in heart rate control, we studied the respective impact of heart rate and temperature lowering on mortality. METHODS Post hoc analysis of the Sepsiscool randomized controlled trial database (NCT00527007). Cooling was applied to maintain normothermia (36.5-37 °C) during 48 h. We assessed the time spent below different thresholds of temperature and heart rate on day 14 mortality. The best threshold was selected by AUC-ROC and tested as a potential mediator of mortality reduction. Mediation analysis was adjusted for severity and treatments influencing temperature and heart rate evolution. Sensitivity analysis was done using only patients with appropriate antimicrobial therapy. RESULTS A total of 197/200 patients with adequate heart rate and temperature monitoring were analyzed. The best threshold differentiating survivors and nonsurvivors was 38.4 °C for temperature and 95 b/min for heart rate. During the 48 h of intervention, cooling significantly increased the time spent with a temperature below 38.4 °C, p = 0.001, and with a heart rate below 95 b/min, p < 0.01. The longer was the time spent with a temperature below 38.4 °C, the lower was the mortality [adjOR 0.17 (0.06-0.49), p = 0.001]. The time spent with a heart rate below 95 b/min was similar in survivors and nonsurvivors [adjOR 0.68 (0.27-1.72), p = 0.42]. Mediation analysis showed that the time spent with a temperature below 38.4 °C was a significant mediator of mortality. CONCLUSION The time spent with a temperature below 38.4 °C was independently associated with patient's outcome and explained 73% of the effect of the randomization on the day 14 mortality. Heart rate lowering was not a mediator of mortality.


title: Local recurrence after microwave thermosphere ablation of malignant liver tumors: results of a surgical series.

text: BACKGROUND Microwave thermosphere ablation is a new treatment modality that creates spherical ablation zones using a single antenna. This study aims to analyze local recurrence associated with this new treatment modality in patients with malignant liver tumors. METHODS This is a prospective clinical study of patients who underwent microwave thermosphere ablation of malignant liver tumors between September 2014 and March 2017. Clinical, operative, and oncologic parameters were analyzed using Kaplan-Meier survival and Cox proportional hazards model. RESULTS One hundred patients underwent 301 ablations. Ablations were performed laparoscopically in 87 and open in 13 patients. Pathology included neuroendocrine liver metastasis (n = 115), colorectal liver metastasis (n = 100), hepatocellular cancer (n = 21), and other tumor types (n = 65). Ninety-day morbidity was 7% with one not procedure-related mortality. Median follow-up was 16 months with 65% of patients completing at least 12 months of follow-up. The rate of local tumor recurrence rate per lesion was 6.6% (20/301). Local tumor, new hepatic, and extrahepatic recurrences were detected in 15%, 40%, and 40% of patients, respectively. Local recurrence rate per pathology was 12% for both colorectal liver metastasis (12/100) and other metastatic tumors (8/65). No local recurrence was observed to date in the neuroendocrine liver metastasis and in the limited number of patients with hepatocellular cancers. Tumor size >3 cm and tumor type were independent predictors of local recurrence. CONCLUSION This is the first study to analyze local recurrence after microwave thermosphere ablation of malignant liver tumors. Short-term local tumor control rate compares favorably with that reported for radiofrequency and other microwave technologies in the literature.


title: Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources.

text: During the recent Ebola crisis in West Africa, individual person-level details of disease onset, transmissions, and outcomes such as survival or death were reported in online news media. We set out to document disease transmission chains for Ebola, with the goal of generating a timely account that could be used for surveillance, mathematical modeling, and public health decision-making. By accessing public web pages only, such as locally produced newspapers and blogs, we created a transmission chain involving two Ebola clusters in West Africa that compared favorably with other published transmission chains, and derived parameters for a mathematical model of Ebola disease transmission that were not statistically different from those derived from published sources. We present a protocol for responsibly gleaning epidemiological facts, transmission model parameters, and useful details from affected communities using mostly indigenously produced sources. After comparing our transmission parameters to published parameters, we discuss additional benefits of our method, such as gaining practical information about the affected community, its infrastructure, politics, and culture. We also briefly compare our method to similar efforts that used mostly non-indigenous online sources to generate epidemiological information.


title: Communication Between Infectious Disease Physicians and US State and Local Public Health Agencies: Strengths, Challenges, and Opportunities.

text: Strong working relationships between infectious disease (ID) physicians and public health have resulted in the early detection of emerging infectious threats. From May 6 through June 5, 2015, we surveyed ID physicians in the Infectious Diseases Society of America's Emerging Infections Network about communications with public health. A total of 688 of 1491 (46%) members completed the survey, 624 (91%) of whom knew how to reach their health department directly for an urgent issue. Only 38 (6%) described communications with their health department as poor. Interest in newer technologies (eg, mobile smartphone applications) showed mixed results. Interest in a smartphone application differed significantly by years of ID experience, with 81 of 146 (55%) respondents with <5 years of ID experience, 172 of 359 (48%) respondents with 5 to 24 years of ID experience, and 61 of 183 (33%) respondents with ≥25 years of ID experience in favor of a smartphone application (P < .001). As more physicians adopt newer communication technologies, health departments should be prepared to incorporate these tools to communicate with ID physicians.


title: Electrogastrography, Near-infrared Spectroscopy, and Acoustics to Measure Gastrointestinal Development in Preterm Babies.

text: OBJECTIVES The aim of the study was to obtain objective measures indicative of gastrointestinal maturity using 3 noninvasive technologies. METHODS Electrogastrography (EGG), abdominal near-infrared spectroscopy (NIRS), and bowel sound/acoustics (AC) monitoring were used simultaneously to obtain physiologic measures of the gastrointestinal system of 18 preterm and 5 term neonates who were tolerating enteral feedings. Measures of EGG slow wave voltage (EGG dominant power) and AC signal amplitude (AC dominant power) were obtained after spectral density analysis. Mean abdominal regional saturations (A-rSO2) were obtained directly from NIRS. The relationship of these 3 measures with postmenstrual age (PMA) was assessed. RESULTS The results of the 3 methods differed depending on whether the measurements were pre- or postprandial. Postprandial EGG dominant power increases with PMA (r = 0.67, P = 0.003), both pre- and postprandial abdominal NIRS mean regional saturation increase with PMA (r = 0.73, P < 0.001 and r = 0.55, P = 0.009), and postprandial AC dominant power (at 300-500 Hz) increases with PMA (r = -0.48, P = 0.025). CONCLUSIONS EGG, abdominal NIRS, and AC, whenever used simultaneously, can provide objective and synergistic measures that correlate with PMA. These findings may be helpful in the assessment of feeding readiness because they reveal quantitative measures suggestive of the developmental process of the gut.


Corrigendum to Canadian Association of Thoracic Radiology/Canadian Association of Radiologists Consensus Statement Regarding Chest Imaging in Suspected and Confirmed COVID-19.


docid: ohsoxchr

title: Gastrointestinal Behavior of Weakly Acidic BCS Class II Drugs in Man--Case Study of Diclofenac Potassium.

text: This study aimed to investigate the gastrointestinal supersaturation and precipitation behavior of a weakly acidic Biopharmaceutics Classification System (BCS) Class II drug in healthy volunteers. For this purpose, a tablet containing 50 mg diclofenac potassium (Cataflam(®)) was predissolved in 240 mL of water and this solution was subsequently orally administered to five healthy volunteers under fasted and fed state conditions with or without concomitant use of a proton-pump inhibitor (PPI) (40 mg esomeprazole, Nexiam(®)). Subsequently, total diclofenac content and dissolved intraluminal drug concentrations as well as drug thermodynamic solubility were determined in gastrointestinal aspirates. In all volunteers, gastric supersaturation resulted in precipitation of diclofenac in the stomach. The extent of precipitation correlated well with gastric pH (r = - 0.78). pH dependency of precipitation was corroborated by the absence of precipitate in the stomach after coadministration of a meal and/or a PPI. Diclofenac was found to be fully dissolved in the duodenum in all test conditions. It can be concluded that substantial pH-dependent gastric precipitation of a weakly acidic BCS Class II drug administered as a solution occurs in humans. With regard to its implications for intestinal absorption, results suggest the instantaneous redissolution of gastric drug precipitate upon transfer to the duodenum.


title: Combined Selective Cerebral Hypothermia and Mechanical Artery Recanalization in Acute Ischemic Stroke: In Vitro Study of Cooling Performance.

text: BACKGROUND AND PURPOSE Therapeutic hypothermia represents a promising neuroprotective treatment for patients with ischemic stroke. Selective, intracarotid blood cooling may initiate rapid and early brain hypothermia, reduce systemic effects, and allow combined endovascular mechanical thrombectomy. For this approach, a balloon cooling catheter system was designed and studied in vitro to optimize its cooling performance. MATERIALS AND METHODS Computational fluid dynamics of blood cooling was performed within the common carotid artery lumen by using 3 different catheter designs (1-, 2-, and 4-balloon array). On the basis of these results, a first catheter prototype was manufactured, and its heat-exchange performance was tested in an artificial in vitro circulation simulating the common carotid artery lumen at different flow rates (inflow temperature of 37°C). RESULTS In the computational fluid dynamics model, the catheter with the 4-balloon array achieved the highest cooling rate of -1.6°C, which may be attributed to disruption of the thermal boundary layers. In the in vitro study, cooling of the blood substitute at flow rates of 400 mL/min (normal common carotid artery flow) and 250 mL/min (reduced common carotid artery flow due to distal MCA occlusion) achieved a temperature drop inside the blood substitute along the cooling balloons of -1.6°C and -2.2°C, respectively. CONCLUSIONS The feasibility of intracarotid blood cooling using a new catheter system was demonstrated in vitro. A serial 4-balloon array led to an optimized cooling capacity approaching optimum target temperatures of mild therapeutic hypothermia. To determine the therapeutic efficacy of combined selective therapeutic hypothermia and mechanical thrombectomy, further in vivo studies by using a model of temporary ischemia with large-vessel occlusion and recanalization are required.


Deadly MERS coronavirus not yet a global concern.


title: Shattered social identity and moral injuries: Work-related conditions in health care professionals during the COVID-19 pandemic.

text: The present article assesses the effects of shattered social identity and moral injuries experienced by health care professionals (HCPs) due to the COVID-19 pandemic. Professional expertise and emotional-cognitive demands as key aspects of HCPs' social identity are introduced, and the effects of moral injuries-in terms of violation of medical-ethical and social-ethical norms-on the mental health of HCPs are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


title: The p48MW Flow Diverter-Initial Human Experience.

text: BACKGROUND AND PURPOSE The use of flow diverters to treat aneurysms arising from small caliber parent vessels has been reported. This article reports the results of the first in experiences with the p48MW (p48 Movable Wire) in humans, a device specifically designed to target vessels 1.75-3 mm in diameter. METHODS This monocentric study retrospectively reviewed the prospectively maintained database to identify all patients treated with the p48MW device between January 2017 and January 2019 at this institution. Patient demographics, aneurysm characteristics, angiographic and clinical follow-up were recorded as well as complications. RESULTS A total of 25 patients (20 female) with an average age of 55 ± 12.9 years (range 34-84) with 25 aneurysms were identified. The majority of the aneurysms was located in the anterior circulation (19/25, 76%). The average aneurysm dome width was 3.98 ± 3.6 mm (range 1.2-13 mm). Complete occlusion was seen in 18/24 (75%) aneurysms with neck remnants in 1/24 (4.2%) and continued aneurysm filling seen in the remaining cases (5/24, 20.8%). Adequate occlusion was seen in 79.2% of aneurysms (Raymond Roy Classification [RRC] grade I or II) during the follow-up period. There was a single technical complication with inappropriate deployment of the first p48MW. There was a single clinical complication (4%); however, the patient made a complete recovery (modified Rankin Scale [mRS] 0) and one patient died secondary to uncontrollable status epilepticus following acute subarachnoid hemorrhage unrelated to the treatment. CONCLUSION The p48MW is safe and effective for the treatment of aneurysms including those arising from distal vessels.


title: Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times (ESCAPE) trial: methodology.

text: ESCAPE is a prospective, multicenter, randomized clinical trial that will enroll subjects with the following main inclusion criteria: less than 12 h from symptom onset, age > 18, baseline NIHSS >5, ASPECTS score of >5 and CTA evidence of carotid T/L or M1 segment MCA occlusion, and at least moderate collaterals by CTA. The trial will determine if endovascular treatment will result in higher rates of favorable outcome compared with standard medical therapy alone. Patient populations that are eligible include those receiving IV tPA, tPA ineligible and unwitnessed onset or wake up strokes with 12 h of last seen normal. The primary end-point, based on intention-to-treat criteria is the distribution of modified Rankin Scale scores at 90 days assessed using a proportional odds model. The projected maximum sample size is 500 subjects. Randomization is stratified under a minimization process using age, gender, baseline NIHSS, baseline ASPECTS (8-10 vs. 6-7), IV tPA treatment and occlusion location (ICA vs. MCA) as covariates. The study will have one formal interim analysis after 300 subjects have been accrued. Secondary end-points at 90 days include the following: mRS 0-1; mRS 0-2; Barthel 95-100, EuroQOL and a cognitive battery. Safety outcomes are symptomatic ICH, major bleeding, contrast nephropathy, total radiation dose, malignant MCA infarction, hemicraniectomy and mortality at 90 days.


Covid-19 pandemic and Nepal.


Single port laparoscopic surgery: concept and controversies of new technique.


title: How much colonic redundancy could be obtained by splenic flexure mobilization in laparoscopic anterior or low anterior resection?

text: BACKGROUND AND OBJECTIVES Splenic flexure mobilization (SFM) is performed to ensure a tension free anastomosis with an adequate resection margin in laparoscopic anterior resection (AR) or low anterior resection (LAR). This retrospective study was performed to determine the amount of colonic redundancy that can be expected by SFM. METHODS Retrospective review of medical record for a total of 203 patients who underwent SFM during laparoscopic AR or LAR for the treatment of sigmoid colon or rectal cancer was performed. RESULTS The obtained redundancy of the colon by SFM was 27.81 ± 7.29 cm from the sacral promontory. The redundancy of the colon by SFM with high ligation of the inferior mesenteric vein (IMV) (29.54 ± 7.17 cm from the sacral promontory) was greater than that with low ligation of the IMV (24.94 ± 6.07 cm from the sacral promontory, P < 0.0001). It took about 9.82% of the total operation time to perform SFM. There was no intraoperative complication during SFM. CONCLUSIONS SFM during laparoscopic AR or LAR is a safe and feasible option. Based on the result of this study, one can gain about 27.81 cm redundancy of the colon by SFM.


title: Massive transfusion and surgical management of iatrogenic aortic laceration associated with cystocentesis in a dog.

text: CASE DESCRIPTION A 4-year-old 29-kg (63.8-lb) spayed female Husky crossbred was referred for emergency treatment because of catastrophic hemorrhagic shock following attempts at cystocentesis for investigation of suspected urinary tract infection. CLINICAL FINDINGS On arrival at the hospital, clinicopathologic assessments revealed rapidly decreasing PCV and worsening hypoproteinemia, compared with findings immediately prior to referral. The dog had severe hyperlactemia. Ultrasonography revealed the presence of free fluid in the abdomen; the fluid appeared to be blood (determined via abdominocentesis). TREATMENT AND OUTCOME Urgent surgical exploration was undertaken. Two small lacerations in the ventral aspect of the abdominal aorta just dorsal to the bladder were identified and repaired. Multiple transfusions of packed RBCs (5 units) and fresh frozen plasma (3 units) were administered, and autotransfusion of blood (1.2 L) from the abdomen was performed. The dog recovered well from surgery and anesthesia, but developed signs of severe pain and swelling of both hind limbs, which were attributed to reperfusion injury following aortic occlusion during surgery. Treatment included administration of S-adenosylmethionine (23 mg/kg [10.5 mg/lb], PO, q 24 h) and analgesia; 5 days after surgery, the hind limb problems had resolved and treatments were discontinued. CLINICAL RELEVANCE In the dog of this report, aortic laceration secondary to cystocentesis was successfully treated with a combination of surgery and massive transfusion; the development of reperfusion injury was an interesting and reversible complication of surgery. The possibility of damage to intra-abdominal structures should be investigated if a dog becomes acutely ill after cystocentesis.


docid: wubwxpiu

title: Creation and benefits of the "COVID Autopsy Listserve".


title: Can Patient-Provider Interpersonal Interventions Achieve the Quadruple Aim of Healthcare? A Systematic Review.

text: BACKGROUND Human connection is at the heart of medical care, but questions remain as to the effectiveness of interpersonal interventions. The purpose of this review was to characterize the associations between patient-provider interpersonal interventions and the quadruple aim outcomes (population health, patient experience, cost, and provider experience). METHODS We sourced data from PubMed, EMBASE, and PsycInfo (January 1997-August 2017). Selected studies included randomized controlled trials and controlled observational studies that examined the association between patient-provider interpersonal interventions and at least one outcome measure of the quadruple aim. Two abstractors independently extracted information about study design, methods, and quality. We characterized evidence related to the objective of the intervention, type and duration of intervention training, target recipient (provider-only vs. provider-patient dyad), and quadruple aim outcomes. RESULTS Seventy-three out of 21,835 studies met the design and outcome inclusion criteria. The methodological quality of research was moderate to high for most included studies; 67% of interventions targeted the provider. Most studies measured impact on patient experience; improvements in experience (e.g., satisfaction, patient-centeredness, reduced unmet needs) often corresponded with a positive impact on other patient health outcomes (e.g., quality of life, depression, adherence). Enhanced interpersonal interactions improved provider well-being, burnout, stress, and confidence in communicating with difficult patients. Roughly a quarter of studies evaluated cost, but the majority reported no significant differences between intervention and control groups. Among studies that measured time in the clinical encounter, intervention effects varied. Interventions with lower demands on provider time and effort were often as effective as those with higher demands. DISCUSSION Simple, low-demand patient-provider interpersonal interventions may have the potential to improve patient health and patient and provider experience, but there is limited evidence that these interventions influence cost-related outcomes.


A Trial of Lopinavir-Ritonavir in Covid-19. Reply.


title: Preoperative biliary drainage for cancer of the head of the pancreas.

text: BACKGROUND The benefits of preoperative biliary drainage, which was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by a tumor of the pancreatic head, are unclear. METHODS In this multicenter, randomized trial, we compared preoperative biliary drainage with surgery alone for patients with cancer of the pancreatic head. Patients with obstructive jaundice and a bilirubin level of 40 to 250 micromol per liter (2.3 to 14.6 mg per deciliter) were randomly assigned to undergo either preoperative biliary drainage for 4 to 6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. Preoperative biliary drainage was attempted primarily with the placement of an endoprosthesis by means of endoscopic retrograde cholangiopancreatography. The primary outcome was the rate of serious complications within 120 days after randomization. RESULTS We enrolled 202 patients; 96 were assigned to undergo early surgery and 106 to undergo preoperative biliary drainage; 6 patients were excluded from the analysis. The rates of serious complications were 39% (37 patients) in the early-surgery group and 74% (75 patients) in the biliary-drainage group (relative risk in the early-surgery group, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). Preoperative biliary drainage was successful in 96 patients (94%) after one or more attempts, with complications in 47 patients (46%). Surgery-related complications occurred in 35 patients (37%) in the early-surgery group and in 48 patients (47%) in the biliary-drainage group (relative risk, 0.79; 95% CI, 0.57 to 1.11; P=0.14). Mortality and the length of hospital stay did not differ significantly between the two groups. CONCLUSIONS Routine preoperative biliary drainage in patients undergoing surgery for cancer of the pancreatic head increases the rate of complications. (Current Controlled Trials number, ISRCTN31939699.)


Is the production of a Covid-19 vaccine using transformed Pasteurella plausible?


title: Lower-body negative pressure restores leg bone microvascular flow to supine levels during head-down tilt.

text: Skeletal unloading and cephalic fluid shifts in microgravity may alter the bone microvascular flow and may be associated with the 1-2% bone loss per month during spaceflight. The purpose of this study was to determine if lower-body negative pressure (LBNP) can prevent microgravity-induced alterations of tibial microvascular flow. Head-down tilt (HDT) simulates the cephalad fluid shift and microvascular flow responses that may occur in microgravity. We hypothesized that LBNP prevents HDT-induced increases in tibial microvascular flow. Tibial bone microvascular flow, oxygenation, and calf circumference were measured during 5 min sitting, 5 min supine, 5 min 15° HDT, and 10 min 15° HDT with 25 mmHg LBNP using photoplethysmography (PPG), near-infrared spectroscopy (NIRS), and strain-gauge plethysmography (SGP). Measurements were made simultaneously. Tibial microvascular flow increased by 36% with 5 min 15° HDT [2.2 ± 1.1 V; repeated-measures ANOVA (RMANOVA) P < 0.0001] from supine (1.4 ± 0.8 V). After 10 min of LBNP in the 15° HDT position, tibial microvascular flow returned to supine levels (1.1 ± 0.5 V; RMANOVA P < 0.001). Tibial oxygenation did not change significantly during sitting, supine, HDT, or HDT with LBNP. However, calf circumference decreased with 5 min 15° HDT (-0.7 ± 0.4 V; RMANOVA P < 0.0001) from supine (-0.5 ± 0.4 V). However, with LBNP calf circumference returned to supine levels (-0.4 ± 0.1 V; RMANOVA P = 0.002). These data establish that simulated microgravity increases tibial microvascular flow and LBNP prevents these increases. The results suggest that LBNP may provide a suitable countermeasure to normalize the bone microvascular flow during spaceflight.


title: Voluntary and electrically-induced muscle fatigue differently affect postural control mechanisms in unipedal stance.

text: The repetition of muscle contractions is likely to generate fatigue which can provoke alterations of postural control. Regulatory mechanisms can be triggered to counteract these alterations. However, these mechanisms would occur only when fatigue is induced through voluntary (VOL) contractions and not with electrically stimulated (ES) contractions. Hence the aim was to compare the effects of VOL and ES fatiguing contractions inducing a similar level of strength loss on unipedal postural control (assessed by means of force platform and EMG measurements), maximal voluntary contraction (MVC) and central activation ratio (CAR) to characterize the alterations induced by both modalities of fatigue and the associated regulatory mechanisms. Results showed that the VOL exercise induced a significant decrease of the CAR whereas the ES exercise did not, thus illustrating that central fatigue was present only after voluntary contractions. The VOL exercise also induced greater postural disturbances and larger regulatory mechanisms than the ES exercise, which also induced postural regulatory mechanisms. The present study reveals that postural control mechanisms are modulated according to the nature of the fatiguing contractions, likely due integration of specific fatigue signals according to the modality of the contraction. Because of a larger neurophysiological impact of VOL than ES fatiguing contractions due to greater central disturbances, VOL exercise-induced larger regulatory mechanisms. Nevertheless, the presence of regulatory mechanisms with ES contractions clearly underlines the ability of the central nervous system to display an accurate motor control following acute externally induced neuromuscular perturbations.


title: Efficacy of coaxial ventilation with a novel endotracheal catheter equipped with a functional cuff: A swine model study.

text: BACKGROUND We have developed an endotracheal catheter with a functional cuff (ECFC) that inflates during inspiration and deflates during expiration. This catheter, together with a regular ICU ventilator, can provide coaxial ventilation. OBJECTIVE The aim of this study was to determine the efficacy of ventilation in adult human-sized swine using an ECFC and a regular ICU ventilator. DESIGN A prospective animal study. SETTING Experimental, Trauma Transplant Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. ANIMALS Eight adult Yorkshire swine, weighing 45 to 50 kg, were studied. INTERVENTIONS To create the ECFC, a 5 cm long latex cuff was placed over the distal side ports of either a 14 or 19-Fr gauge endotracheal catheter and a 1 cm long piece of plastic tube was inserted into the tip of the endotracheal catheter to create an internal resistance. The ECFC was placed into the trachea and the proximal end of the ECFC was connected to an ICU ventilator in pressure-control mode, with peak pressures set at either 25, 50 or 70 cmH2O. MAIN OUTCOME MEASURES Tidal volume was calculated using plethysmography. RESULTS During pressure control ventilation with the 14-Fr gauge ECFC at set inspiratory pressures of 25, 50 and 75 cmH2O, the tidal volumes generated were 209 ± 36, 309 ± 61 and 367 ± 85 ml, respectively, and with the 19-Fr gauge ECFC these were 277 ± 51, 442 ± 91 and 538 ± 123 ml, respectively. No complications were observed. CONCLUSION An ECFC combined with a regular pressure-controlled ICU ventilator can produce adequate tidal volumes in adult human-sized swine. Our results establish the feasibility of ventilation with this new alternative technique. The safety and advantages of such a technique remain to be determined in humans.


title: Pathological Findings of Postmortem Biopsies From Lung, Heart, and Liver of 7 Deceased COVID-19 Patients.

text: Background. A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been affecting almost all nations around the world. Most infected patients who have been admitted to intensive care units show SARS signs. In this study, we aimed to achieve a better understanding of pathological alterations that take place during the novel coronavirus infection in most presumed affected organs. Methods. We performed postmortem core needle biopsies from lung, heart, and liver on 7 deceased patients who had died of coronavirus disease 2019. Prepared tissue sections were observed by 2 expert pathologists. Results. Diffuse alveolar damage was the main pathologic finding in the lung tissue samples. Patients with hospitalization durations of more than 10 days showed evidence of organization. Multinucleated cells in alveolar spaces and alveolar walls, atypical enlarged cells, accumulation of macrophages in alveolar spaces, and congestion of vascular channels were the other histopathologic alteration of the lung. None of our heart biopsy samples met the criteria for myocarditis. Liver biopsies showed congestion, micro- and macro-vesicular changes, and minimal to mild portal inflammation, in the majority of cases. Conclusions. Similar to the previous coronavirus infection in 2003, the main pathologic finding in the lung was diffuse alveolar damage with a pattern of organization in prolonged cases. The SARS-CoV-2 infection does not cause myocarditis, and the ischemia of myocardium is the most probable justification of the observed pathologic changes in the heart. Liver tissue sections mostly showed nonspecific findings; however, ischemia of the liver can be identified in some cases.


docid: cgcaerjy

title: The tumor marker human placental protein 11 is an endoribonuclease.

text: Human PP11 (placental protein 11) was previously described as a serine protease specifically expressed in the syncytiotrophoblast and in numerous tumor tissues. Several PP11-like proteins were annotated in distantly related organisms, such as worms and mammals, suggesting their involvement in evolutionarily conserved processes. Based on sequence similarity, human PP11 was included in a protein family whose characterized members are XendoU, a Xenopus laevis endoribonuclease involved in small nucleolar RNA processing, and Nsp15, an endoribonuclease essential for coronavirus replication. Here we show that the bacterially expressed human PP11 displays RNA binding capability and cleaves single stranded RNA in a Mn(2+)-dependent manner at uridylates, to produce molecules with 2',3'-cyclic phosphate ends. These features, together with structural and mutagenesis analyses, which identified the potential active site residues, reveal striking parallels to the amphibian XendoU and assign a ribonuclease function to PP11. This newly discovered enzymatic activity places PP11-like proteins in a completely new perspective.


title: Tumors affecting the spinal cord of cats: 85 cases (1980-2005).

text: OBJECTIVE To determine the prevalence of lymphosarcoma and other tumors affecting the spinal cord of cats and to relate specific types of tumors with signalment, history, and clinical findings. DESIGN Retrospective case series. ANIMALS 85 cats with tumors affecting the spinal cord. PROCEDURES Medical records of cats with histologically confirmed primary or metastatic tumors of the spinal cord or tumors causing spinal cord disease by local extension from adjacent tissues examined between 1980 and 2005 were reviewed. Data on signalment; clinical history; results of neurologic examination, diagnostic imaging, and clinical pathologic evaluation; and location of tumor within the spinal cord were obtained from medical records and analyzed by use of logistic regression models. RESULTS Lymphosarcoma was the most common tumor and affected the spinal cord in 33 (38.8%) cats, followed by osteosarcoma in 14 (16.5%) cats. Cats with lymphosarcoma were typically younger at initial examination, had a shorter duration of clinical signs, and had lesions in more regions of the CNS than did cats with other types of tumors. In 22 of 26 (84.6%) cats with lymphosarcoma, the tumor was also found in extraneural sites. CONCLUSIONS AND CLINICAL RELEVANCE Data for spinal cord tumors in this population of cats were analyzed by logistic regression analysis, which effectively distinguished cats with lymphosarcoma from cats with other types of tumors. Additional clinical information reported here will help to increase the index of suspicion or definitive antemortem diagnosis of spinal cord tumors of cats.


title: Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans.

text: Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-α and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.


title: Long-distance RNA-RNA interactions in the coronavirus genome form high-order structures promoting discontinuous RNA synthesis during transcription.

text: Coronavirus (CoV) transcription requires a high-frequency recombination process that links newly synthesized minus-strand subgenomic RNA copies to the leader region, which is present only once, at the 5' end of the genome. This discontinuous RNA synthesis step is based on the complementarity between the transcription-regulating sequences (TRSs) at the leader region and those preceding each gene in the nascent minus-strand RNA. Furthermore, the template switch requires the physical proximity of RNA genome domains located between 20,000 and 30,000 nucleotides apart. In this report, it is shown that the efficacy of this recombination step is promoted by novel additional long-distance RNA-RNA interactions between RNA motifs located close to the TRSs controlling the expression of each gene and their complementary sequences mapping close to the 5' end of the genome. These interactions would bring together the motifs involved in the recombination process. This finding indicates that the formation of high-order RNA structures in the CoV genome is necessary to control the expression of at least the viral N gene. The requirement of these long-distance interactions for transcription was shown by the engineering of CoV replicons in which the complementarity between the newly identified sequences was disrupted. Furthermore, disruption of complementarity in mutant viruses led to mutations that restored complementarity, wild-type transcription levels, and viral titers by passage in cell cultures. The relevance of these high-order structures for virus transcription is reinforced by the phylogenetic conservation of the involved RNA motifs in CoVs.


title: Outbreak science: recent progress in the detection and response to outbreaks of infectious diseases.

text: The frequency of reported outbreaks of infectious diseases has increased over the past 3 decades, with predictions that this rise will continue. Outbreak response continues to follow nine basic principles: establish the presence of an outbreak, verify the diagnosis, make a case definition, find cases and contacts, conduct basic epidemiology, test hypotheses, institute control measures, communicate the situation and establish ongoing surveillance. Within each of these areas, significant advances have been made over the past 5 years using progress in digital, laboratory, epidemiology and anthropological equipment or techniques. Irrespective of these, future outbreaks of high-consequence are inevitable, and vigilance and preparation must continue in order to prevent significant mortality, morbidity and socio-economic crisis.


docid: mfswbehl

title: Public Understanding of Medical Countermeasures.

text: Medical countermeasures, including new drugs and vaccines, are necessary to protect the public's health from novel diseases and terrorist threats. Experience with the 2001 anthrax attack and the 2009 H1N1 pandemic suggest that there is limited willingness to accept such drugs and that minority groups may respond differently from others. We conducted 148 intercept interviews in the metropolitan Washington, DC, area, examining 2 hypothetical scenarios: a new respiratory virus and public exposure to high levels of radiation. Findings provide insights into key factors that affect whether diverse members of the public comply with recommended protective actions like taking emergency authorized vaccines. These insights can help improve how public health practitioners communicate during uncertain times.


Protect against market exclusivity in the fight against COVID-19.


title: A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial.

text: OBJECTIVES The study investigated the efficacy and safety of a balloon expandable, sirolimus-eluting stent (SES) in patients with symptomatic infrapopliteal arterial disease. BACKGROUND Results of infrapopliteal interventions using balloon angioplasty and/or bare stents are limited by a relatively high restenosis rate, which could be potentially improved by stabilizing the lesion with a SES. METHODS Two hundred patients (total lesion length 27 ± 21 mm) were randomized to infrapopliteal SES stenting or percutaneous transluminal balloon angioplasty (PTA). The primary endpoint was 1-year in-segment binary restenosis by quantitative angiography. RESULTS Ninety-nine and 101 patients (mean age 73.4 years; 64% diabetics) were randomized to SES and PTA, respectively (8 crossover bailout cases to SES). At 1 year, there were lower angiographic restenosis rates (22.4% vs. 41.9%, p = 0.019), greater vessel patency (75.0% vs. 57.1%, p =0.025), and similar death, repeat revascularization, index-limb amputation rates, and proportions of patients with improved Rutherford class for SES versus PTA. CONCLUSIONS SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease.


Peribronchial Consolidation with Surrounding Ground-Glass Opacity in COVID-19 Pneumonia: 3D Reconstruction of a Chest Computed Tomography.


Acute Start Peritoneal Dialysis during the COVID-19 Pandemic: Outcomes and Experiences.


title: Providing care for the 99.9% during the COVID-19 pandemic: How ethics, equity, epidemiology, and cost per QALY inform healthcare policy.

text: Managing healthcare in the Coronavirus Disease 2019 (COVID-19) era should be guided by ethics, epidemiology, equity, and economics, not emotion. Ethical healthcare policies ensure equitable access to care for patients regardless of whether they have COVID-19 or another disease. Because healthcare resources are limited, a cost per Quality Life Year (QALY) approach to COVID-19 policy should also be considered. Policies that focus solely on mitigating COVID-19 are likely to be ethically or financially unsustainable. A cost/QALY approach could target resources to optimally improve QALYs. For example, most COVID-19 deaths occur in long-term care facilities, and this problem is likely better addressed by a focused long-term care reform than by a society-wide non-pharmacological intervention. Likewise, ramping up elective, non-COVID-19 care in low prevalence regions while expanding testing and case tracking in hot spots could reduce excess mortality from non-COVID-19 diseases and decrease adverse financial impacts while controlling the epidemic. Globally, only ∼0.1% of people have had a COVID-19 infection. Thus, ethical healthcare policy must address the needs of the 99.9%.


title: Nanomedicine and infectious diseases.

text: The First International Conference on Infectious Diseases and Nanomedicine congress facilitated the mixing of researchers in various fields of nanomedicine and infectious diseases, bringing together researchers from the fields of physics and chemistry, on the production of nanoparticles and researchers from various fields of microbiology where these nanoparticles have practical applications. The manufacture and applications of nanoparticles was one of the main themes of the congress, with much emphasis on the use of nanoparticles for the treatment of cancer. The ever increasing problems and concerns around antibiotic resistance also featured prominently in the congress. Various interesting presentations on human viruses were also presented during this congress.


docid: eyvywyob

title: Direct costs of low respiratory infection due to RSV in children under one year.

text: INTRODUCTION Considering the high prevalence of respiratory infections in hospitalized infants with Respiratory Syncytial Virus (RSV), the objective of this study is to determine the direct costs of this infection. PATIENTS AND METHOD Prospective longitudinal study in infants under one year of age hospitalized due to RSV during 2015. The patients were divided into 2 groups, Group 1 pa tients without risk factors and Group 2 patients with risk factors (prematurity, oxygen dependence, bronchopulmonary dysplasia, heart disease, immunocompromised patients), comparing each other variables such as nutritional status, gender, breastfeeding, discharge diagnosis, radiological diagno sis, length of hospital stay, among others. Direct costs for hospitalization were estimated according to the fees of the National Health Fund (FONASA) and the Modality of Institutional Care (MAI). RESULTS The total patients admitted in the period were 260: 234 (90%) in Group 1 and 26 (10%) in Group 2. The average hospital stay for Group 1 was 7.3 days (SD+5.1) with a median of 6 days, and 13.6 days (SD+16.3) for Group 2 with a median of 7 days (p < 0.05). The direct costs associated with RSV hospitalization were on average CLP $ 413,529 (US$ 632.1) for Group 1, and CLP $ 744,260 (US$ 1,137.6) for Group 2 (p < 0.05). There was also statistically significant higher cost for Group 2 due to tests and drugs (p < 0.05) and costs per day of hospital stay (p < 0.05). CONCLUSION These values, known for the first time in the national reality, confirm the high cost of these infections and particularly in risk groups.


Face masks in the covid-19 crisis: caveats, limits, and priorities.


20-Year Synthetic Biology Research Roadmap: Implications for Vaccine Development and Future Research.


Subxiphoid pneumonectomy: the new frontier?


title: Thrombus Embolisation: Prevention is Better than Cure.

text: Thrombus embolisation complicating primary percutaneous coronary intervention in ST-elevation myocardial infarction is associated with an increase in adverse outcomes. However, there are currently no proven recommendations for intervention in the setting of large thrombus burden. In this review, we discuss the clinical implications of thrombus embolisation and angiographic predictors of embolisation, and provide an update of current evidence for some preventative strategies, both pharmacological and mechanical, in this setting.


title: Respiratory viruses and influenza-like illness: a survey in the area of Rome, winter 2004-2005.

text: Limited information is available on the viral aetiology of influenza-like illness (ILI) in Southern European countries. Hereby we report the main findings of a survey conducted in the area of Rome during the 2004-2005 winter season. ILI cases were defined as individuals with fever >37.5°C and at least one constitutional symptom and one respiratory symptom, recruited during the survey period. Influenza and other respiratory viruses were identified using polymerase chain reaction (PCR) on throat swabs. Basic individual information was collected through a standard form. Of 173 ILI cases enrolled, 74 tested positive for one virus, and two tested positive for two viruses. Overall, 33.5% of the cases were positive for influenza viruses, 5.2% for adenoviruses, 3.5% for parainfluenza viruses, 1.7% for coronaviruses, and 1.2% for the respiratory syncitial virus. The proportion of influenza virus detection was higher in the 'high influenza activity' period. The distribution of viral agents varied across age groups, influenza viruses being more likely to be detected in younger patients. Viral pathogens were identified in less than 50% of ILI cases occurred during a high activity influenza season. The detection of other than influenza viruses was sporadic, without evidence of large outbreaks due to specific agents.


COVID-19: Nephrology preparedness checklist.


title: Stewart-Bluefarb syndrome: Report of five cases and a review of literature.

text: Stewart-Bluefarb syndrome is a rare angioproliferative disorder characterised by acroangiodermatitis associated with an underlying arteriovenous shunt. This condition should be differentiated from acroangiodermatitis of Mali classically described in association with chronic venous insufficiency. Patients with Stewart-Bluefarb syndrome typically present with lower leg pigmented macules, papules and plaques that can coalesce to form larger confluent patches of pigmentation. Recognition of Stewart-Bluefarb syndrome may be difficult or delayed as the cutaneous manifestations may resemble a variety of other dermatological conditions. Most commonly, acroangiodermatitis may be confused with Kaposi's sarcoma and the condition is often referred to as 'Pseudo-Kaposi's sarcoma'. Acroangiodermatitis may also resemble or coexist with pigmentation of chronic venous insufficiency. As seen in this report, acroangiodermatitis may also be clinically confused with the 'cavernous' form of a capillary malformation. Here, we describe five patients with Stewart-Bluefarb syndrome. In one female and two male patients the diagnosis was delayed as the acroangiodermatitis closely resembled other conditions. All underlying arterio-venous communications were initially diagnosed on duplex ultrasound and confirmed with magnetic resonance angiography. Four patients were found to have a congenital arterio-venous malformation while one was diagnosed with a post-thrombotic arterio-venous fistula. Management included observation and intervention using a variety of techniques including percutaneous or trans-catheter embolisation, endovenous laser, radiofrequency ablation and foam ultrasound guided sclerotherapy. This case series highlights the challenges involved in the diagnosis and management of Stewart-Bluefarb syndrome. Given the local and systemic sequelae of high flow shunts, correct diagnosis and early detection of the underlying arterio-venous abnormality is crucial in the long-term management of these patients and in preventing the associated complications.


title: Evaluation of the safety and feasibility of laparoscopic total gastrectomy in clinical stage I gastric cancer patients.

text: BACKGROUND This retrospective study was designed to assess the feasibility of laparoscopic total gastrectomy (LTG) in clinical stage I gastric cancer patients, and validate the appropriateness of the widespread adoption of LTG for experienced open surgeons. METHODS Eighty-eight patients with clinical stage I gastric cancer underwent LTG in our hospitals (n = 55) and affiliated hospitals (n = 33). Esophagojejunostomy was performed intracoporeally using a circular stapler with an incision in the left upper abdomen. We investigated the patients' clinicopathologic factor, and evaluated the effect of hospital volume on short-term outcomes. RESULTS Fixed insertion of the anvil head was successfully achieved in all patients (lift-up method in 58 patients and transoral method in 28 patients), although 2 patients were converted to open surgery. The approach using a circular stapler through a small incision from the upper left quadrant of the abdomen facilitated a good laparoscopic visual field for the plane of the esophagojejunostomy. Fourteen patients developed Clavien-Dindo classification grade II or more postoperative complications, and the overall operative morbidity rate was 15.9 %. No anastomotic leakage was encountered in this series. No significant difference was observed in clinical outcomes between patients in the high- and low-volume hospital groups. CONCLUSIONS Laparoscopic total gastrectomy can be performed safely on clinical stage I gastric cancer patients by surgeons with sufficient experience in open gastrectomy and therefore represents a feasible procedure that is not clinically impacted by hospital volume.


title: Quantifying uncertainty in the chemical master equation.

text: We describe a novel approach to quantifying the uncertainty inherent in the chemical kinetic master equation with stochastic coefficients. A stochastic collocation method is coupled to an analytical expansion of the master equation to analyze the effects of both extrinsic and intrinsic noise. The method consists of an analytical moment-closure method resulting in a large set of differential equations with stochastic coefficients that are in turn solved via a Smolyak sparse grid collocation method. We discuss the error of the method relative to the dimension of the model and clarify which methods are most suitable for the problem. We apply the method to two typical problems arising in chemical kinetics with time-independent extrinsic noise. Additionally, we show agreement with classical Monte Carlo simulations and calculate the variance over time as the sum of two expectations. The method presented here has better convergence properties for low to moderate dimensions than standard Monte Carlo methods and is therefore a superior alternative in this regime.


title: Biomarker-guided screening of Juzen-taiho-to, an oriental herbal formulation for immunostimulation.

text: Juzen-taiho-to is an immunostimulatory herbal formulation that is clinically used in East Asia for cancer patients undergoing chemotherapy and radiation. The formulation stimulates various leukocytes, including T, B, and NK cells and macrophages. Although Juzen-taiho-to is known to contain numerous compounds with various pharmacological activities, it is not clear which compounds are responsible for the stimulation of individual cell types. Here, we conducted what we call "biomarker-guided screening" to purify compounds responsible for the macrophages stimulatory activity. To this end, gene expression was analyzed by a DNA array for macrophages treated with Juzen-taiho-to and DMSO (vehicle control), which identified intercellular adhesion molecule 1 as a biomarker of macrophage stimulation by Juzen-taiho-to. A quantitative reverse transcription polymerase chain reaction assay of intercellular adhesion molecule 1 was then used to guide the purification of active compounds. The screening resulted in the purification of a glycolipid mixture, containing β-glucosylceramides. The glycolipid mixture potently stimulated intercellular adhesion molecule 1 expression in primary dendritic cells as well as in primary CD14+ (macrophages) cells. The identification of this glycolipid mixture opens up an opportunity for further studies to understand how plant-derived glycolipids stimulate macrophages and dendritic cells in a safe and effective manner as demonstrated by Juzen-taiho-to.


Temperature and COVID-19: India.


title: A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models.

text: BACKGROUND Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. METHODS In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. RESULTS Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). CONCLUSIONS The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use.


title: Laparoscopic common bile duct exploration. Lessons learned after 200 cases.

text: INTRODUCTION Laparoscopic common bile duct exploration (LCBDE) is a reliable, reproducible and cost-effective treatment for common bile duct stones. Several techniques have been described for choledochotomy closure. AIMS To present our experience and the lessons learned in more than 200 cases of LCBDE. PATIENTS AND METHODS Between January 1999 and July 2012, 206 patients with common bile duct stones underwent LCBDE. At the beginning of the series, we performed the closure of the CBD over a T-tube (36 patients), subsequently we favoured closure over an antegrade stent (133 patients) but due to a high incidence of acute pancreatitis in the last 16 patients we have performed primary closure. RESULTS The 3 closure groups were matched for age and sex. Jaundice was the most frequent presentation. A total of 185 (88,5%) patients underwent choledochotomy whereas in 17 (8,7%) patients the transcystic route was used. The group that underwent choledochotomy had a larger size of stones compared to the transcystic group (9,7 vs 7,6mm). In the stented group we found an 11,6% incidence of pancreatitis and 26,1% of hyperamylasemia. In the primary closure group we found a clear improvement of complications and hospital stay. The increased experience of the surgeon and age (younger than 75) had a positive impact on mortality and morbidity. CONCLUSIONS Primary closure of the common bile duct after LCBDE seems to be superior to closure over a T tube and stents. The learning curve seems to have a positive impact on the outcomes making it a safe and reproducible technique especially for patients aged under 75.


title: Endovascular Interventions for Acute Ischemic Stroke: A Review of Recent Trials.

text: OBJECTIVE To review recent endovascular intervention trials for acute ischemic stroke. DATA SOURCES Recent, randomized controlled trials of endovascular interventions for acute ischemic stroke were identified. The search terms "endovascular" AND "stroke" were used and filter for "randomized controlled trial" was applied; the period searched was January 1, 2013, to October 31, 2015. STUDY SELECTION AND DATA EXTRACTION Randomized controlled trials of endovascular interventions in acute ischemic stroke published within the past 3 years (2013-2015). DATA SYNTHESIS A total of 8 trials are reviewed: 3 trials published in 2013 demonstrated neutral results for endovascular interventions, and 5 trials published in 2015 demonstrated positive results for endovascular interventions. Potential reasons for the change in outcomes include better patient selection and improvement indevice technology. Patient selection improvements included selecting patients with salvageable brain tissue with an identifiable thrombus on perfusion imaging. The major improvement in device technology was the introduction of the Solitaire Flow Restoration stent retriever and the Trevo stent retriever, both of which have improved recanalization rates compared with earlier devices. Adjunctive medication considerations include the mode of sedation (general or conscious), intraprocedural anticoagulation with heparin, and intra-arterial tissue plasminogen activator. CONCLUSIONS The use of endovascular devices for treating acute ischemic stroke is likely to increase as more centers become capable of integrating them into their stroke programs. It is important for pharmacists to understand the trials that evaluated endovascular interventions because differences exist with respect to device, adjunctive medication, and patient selection, all of which affect patient outcomes.


title: Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mice.

text: Damage of oligodendrocytes after ischemia has negative impact on white matter integrity and neuronal function. In this work, we explore whether Netrin-1 (NT-1) overexpression facilitates white matter repairing and remodeling. Adult CD-1 mice received stereotactic injection of adeno-associated virus carrying NT-1 gene (AAV-NT-1). One week after gene transfer, mice underwent 60 minutes of middle cerebral artery occlusion. The effect of NT-1 on neural function was evaluated by neurobehavioral tests. Proliferated oligodendrocyte progenitor cells (OPCs), newly matured oligodendrocytes, and remyelination were semi-quantified by immunohistochemistry. The role of NT-1 in oligodendrogenesis was further explored by examining specific NT-1 receptors and their function. Netrin-1 overexpression was detected in neurons and astrocytes 2 weeks after AAV-NT-1 gene transfer and significantly improved the neurobehavioral outcomes compared with the control (P<0.05). In comparison with the control, proliferated OPCs, newly matured oligodendrocytes, and remyelination were greatly increased in the ipsilateral hemisphere of AAV-NT-1-transduced mice. Furthermore, both NT-1 receptors deleted in colorectal carcinoma and UNC5H2 were expressed on OPCs whereas only UNC5H2 was expressed in myelinated axons. Our study indicated that NT-1 promoted OPC proliferation, differentiation, and increased remyelination, suggesting that NT-1 is a promising factor for white matter repairing and remodeling after ischemia.


title: Single-Port Laparoscopic Liver Resection: Largest Turkish Experience.

text: Single-port laparoscopic surgery has the advantage of a hidden scar and reduced abdominal wall trauma. Although single-port laparoscopic surgery is widely performed for other organs, its application is very limited for liver resection. Here, we report our experience with nine patients who underwent single-port laparoscopic liver resection. Nine patients underwent single-port laparoscopic liver resection for the indications of hydatid cyst, hepatocellular carcinoma, and colorectal cancer liver metastasis. Nine patients were successfully treated with single-port laparoscopic surgery. The operative time was between 60 and 240 min. The only operative complication was bleeding up to 650 mL in a patient with cirrhosis. No postoperative complications occurred. All patients were discharged earlier than usual. Single-port laparoscopic liver surgery is a challenging surgery. Surgeon with the experience of laparoscopic liver surgery should perform the single-port laparoscopic liver surgery. It is technically feasible with a good outcome in well-selected patients. Initial cases must be benign lesions to avoid jeopardizing oncological safety.


title: Monitoring COVID-19 through Trends in Influenza-like Illness and Laboratory-confirmed Influenza and COVID-19 - New York State, excluding New York City, January 1 - April 12, 2020.

text: Innovative monitoring approaches are needed to track the COVID-19 epidemic and potentially assess the impact of community mitigation interventions. In this report, we present temporal data on influenza-like illness, influenza diagnosis and COVID-19 cases for all four regions of New York State through the first six weeks of the outbreak.