Routine postoperative noninvasive respiratory support and pneumonia after elective surgery: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Postoperative pulmonary complications, including pneumonia, are a substantial cause of morbidity. We hypothesised that routine noninvasive respiratory support was associated with a lower incidence of pneumonia after surgery. METHODS: Systematic review and meta-analysis of RCTs comparing the routine use of continuous positive airway pressure (CPAP), noninvasive ventilation (NIV), or high-flow nasal oxygen (HFNO) against standard postoperative care in the adult population. We searched MEDLINE (PubMed), EMBASE, and CENTRAL from the start of indexing to July 27, 2021. Articles were reviewed and data extracted in duplicate, with discrepancies resolved by a senior investigator. The primary outcome was pneumonia, and the secondary outcome was postoperative pulmonary complications. We calculated risk difference (RD) with 95% confidence intervals using DerSimonian and Laird random effects models. We assessed risk of bias using the Cochrane risk of bias tool. RESULTS: From 18 513 records, we included 38 trials consisting of 9782 patients. Pneumonia occurred in 214/4403 (4.9%) patients receiving noninvasive respiratory support compared with 216/3937 (5.5%) receiving standard care (RD -0.01 [95% confidence interval: -0.02 to 0.00]; I2=8%; P=0.23). Postoperative pulmonary complications occurred in 393/1379 (28%) patients receiving noninvasive respiratory support compared with 280/902 (31%) receiving standard care (RD -0.11 [-0.23 to 0.01]; I2=79%; P=0.07). Subgroup analyses did not identify a benefit of CPAP, NIV, or HFNO in preventing pneumonia. Tests for publication bias suggest six unreported trials. CONCLUSION: The results of this evidence synthesis do not support the routine use of postoperative CPAP, NIV, or HFNO to prevent pneumonia after surgery in adults. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42019156741.

Outcomes of sympathectomy and vascular bypass for digital ischaemia in connective tissue disorders.

All patients (36 hands) with connective tissue disorders who underwent periarterial sympathectomy of the hand alone or in conjunction with vascular bypass at our institution between 1995-2013 were reviewed. The durable resolution of ulcers was significantly higher in patients treated by periarterial sympathectomy and bypass than in patients treated by periarterial sympathectomy alone. Although there were more digital amputations in patients treated by periarterial sympathectomy alone, the difference was not statistically significant. Vascular bypass in conjunction with sympathectomy may be better than sympathectomy alone in patients with digital ischaemia related to connective tissue disorders. LEVEL OF EVIDENCE: IV.

Induction of antiviral cytotoxic T cells by plasmacytoid dendritic cells for adoptive immunotherapy of posttransplant diseases.

Virus-associated hematologic malignancies (EBV lymphoproliferative disease) and opportunistic infections (CMV) represent a major cause of hematopoietic stem cell and solid organ transplantation failure. Adoptive transfer of antigen-specific T lymphocytes appears to be a major and successful immunotherapeutic strategy, but improvements are needed to reliably produce high numbers of virus-specific T cells with appropriate requirements for adoptive immunotherapy that would allow extensive clinical use. Since plasmacytoid dendritic cells (pDCs) are crucial in launching antiviral responses, we investigated their capacity to elicit functional antiviral T-cell responses for adoptive cellular immunotherapy using a unique pDC line and antigens derived from Influenza, CMV and EBV viruses. Stimulation of peripheral blood mononuclear cells from HLA-A*0201(+) donors by HLA-A0201 matched pDCs pulsed with viral-derived peptides triggered high levels of multi-specific and functional cytotoxic T-cell responses (up to 99% tetramer(+) CD8 T cells) in vitro. Furthermore, the central/effector memory cytotoxic T cells elicited by the pDCs strongly display antiviral activity upon adoptive transfer into a humanized mouse model that mimics a virus-induced malignancy. We provide a simple and potent method to generate virus-specific CTL with the required properties for adoptive cellular immunotherapy of post-transplant diseases.

[Femur reconstruction using combined autologous fibula transfer and humeral allograft]. / Femurrekonstruktion mit kombiniertem autologem Fibulatransfer und Humerus-Allograft.

Wide resection far into the femoral metaphysis may be required to treat malignant bone tumors in the pediatric and adolescent patient population. Biological reconstruction using a free, vascularized fibular graft is a well-established surgical technique. A short remaining femoral medullary canal and a relatively small fibula diameter can make fixation of the vascularized bone transfer difficult. Stable fixation and short fusion times, however, can be achieved with the use of an additional humeral allograft and plate osteosynthesis.

[GENiusVac, a novel antitumor vaccine strategy based on allogeneic plasmacytoid dendritic cells]. / GENiusVac, une stratégie vaccinale antitumorale innovante basée sur des cellules dendritiques plasmocytoïdes allogéniques.

The development of effective vaccines against cancer and viruses still remains a challenge. Many immunotherapeutic strategies have been developed but without sufficient therapeutic success. Plasmacytoid dendritic cells (pDC) play a crucial role in antitumor and antiviral responses. Despite their outstanding functional properties, their therapeutic potential has not yet been worked out. We propose a new immunotherapeutic strategy based on a pDC cell line irradiated and pulsed with tumor or viral antigens. GENiusVac allows the induction of multispecific and highly functional cytotoxic cell responses directed against viral or tumor targets. We demonstrated the potential of this strategy in vitro, its therapeutic efficacy in vivo in a humanized mouse model, and its clinical relevance ex vivo from melanoma patients' cells. GENiusVac highlights pDCs as potent vector of immunotherapy and provide a way to exploit them in cell therapy to fight cancer or chronic viral infections.

[Quality control of defrosted cord blood units: results from an inter-laboratory study]. / Contrôle de qualité des greffons de sang placentaire décongelés : résultats d'une étude multicentrique.

PURPOSE: Today, haematopoietic stem cell graft from placental blood concerns more than 15 % of allogeneic grafts. An inter-laboratory study of the quality control of defrosted cord blood units has been coordinated by the French society for cell and tissue bioengineering (SFBCT), with the cord blood bank of Bourgogne Franche-Comté and controlled by the French health products safety agency (Afssaps). The aim of this study is to ensure the inter-laboratory reproducibility of the quality controls practised by the banks during defrosting. The cellular outputs were analyzed according to the defrosting techniques, according to the method used in flow cytometry: single-platform (SP) versus double-platform (DP), or the product nature, i.e. in total blood or miniaturized. METHODS: Forty-two units of placental blood (USP), which were out of range were provided for defrosting to 14 participating sites. USP were defrosted and controlled according to the procedures of each bank. Once the USP is defrosted, a part of the product was controlled by the site and the other part by Afssaps. Following controls were carried out: numeration of the total nucleated cells (TNC) and of CD34+ cells (made by a SP method in Afssaps) and functional assay. RESULTS: Concerning TNC, the defrosting sites obtained a cellular output of 94 %+/-28 in day 0 compared with an output of 72 %+/-24 in Afssaps showing a rather good stability of the USP transmitted with an average deviation of 23 %+/-22. The freezing process with or without reduction of volume does not affect this variation. Concerning the numeration of CD34+ cells, the average deviation between the participating sites and Afssaps was 29 %+/-23 compared with 21 %+/-16 for the sites using a SP method against 47 %+/-25 for those using a DP method. The CD34+ outputs are equal to 82 % +/- 60 in day 0 for the participating sites against 52 %+/-20 for Afssaps. For the sites using a DP method, it is stressed that this output is particularly high with a rate of 126 %+/-90 (n=15) whereas it is 62 %+/-20 (n=32) for the sites using a SP method. CONCLUSION: These results underline a good stability of viable CD34+ cells and a greater reliability of the SP methods for the CD34+ cell numeration for these defrosted USP. Lastly, the results of the functional assay regarding the average clonogenicities (equal to 15 %) reinforce the conclusions on the quality of the defrosted products.

[Extracorporeal photochemotherapy or immunotherapy using cells modified by photochemistry]. / La photochimiothérapie extracorporelle ou l'immunothérapie par cellules modifiées par photochimie.

Extracorporeal photochemotherapy (ECP) is an autologous cell therapy used for the treatment of diseases involving pathogenic cells: cutaneous T-cell lymphoma, organ rejection and graft versus host disease. During an ECP procedure, patients receive a cellular product consisting of autologous mononuclear cells, containing the pathogenic cells, treated with a photosensitising agent and an UV-A radiation. The aim of the treatment is to induce a specific immune reaction modulating the activity of untreated pathogenic lymphocytes responsible for the disease and therefore an improvement of clinical manifestations. The precise mechanisms of action remain to be defined in humans. Its efficacy coupled with the absence of side effects could lead to decrease the use of immunosuppressive drugs. PCE appears as an immunotherapy using cells modified by photochemistry, which allows specific immune modulation of pathogenic lymphocytes.

Modification of thiol functionalized aptamers by conjugation of synthetic polymers.

Aptamers are known for their short in vivo circulating half-life and rapid renal clearance. Their conjugation to poly(ethylene glycol) (PEG) is a way to improve their residence in the body. Two aptamers (AptD and AptF), having a disulfide protected thiol modification on the 3' end, have been conjugated to maleimide activated PEGs of various molecular weights and structures (linear PEG20; branched PEG20 and 40; PolyPEG17, 40, and 60 kDa). The high yield coupling (70-80% in most of the cases) could be achieved using immobilized tris[2-carboxyethyl]phosphine hydrochloride (TCEP) as reducing agent at pH 4. The affinity of PEGylated AptD for its target was reduced by conjugation to linear PEG20 and branched PEG40, but not to branched PEG20 and PolyPEGs. This work demonstrates an alternative approach to PEGylation of aptamers, and that the effect of PEG on the affinity for the target varies according to the structure and conformation of the synthetic polymer.

Splenic lymphoma in a short-beaked echidna (Tachyglossus aculeatus).

A 23-year-old, male short-beaked echidna (Tachyglossus aculeatus) housed at a North American zoo was successfully treated for flea-associated anaemia, but subsequently died. Cause of death was presumptive septicaemia secondary to splenic lymphoma. This is only the fifth case of neoplasia reported in this monotreme species, and the first from outside of Australia.

Mycothiol disulfide reductase: a continuous assay for slow time-dependent inhibitors.

Mycothiol (MSH) is the principal low-molecular-weight thiol, unique to mycobacteria and other actinomycetes, that performs a role analogous to glutathione found in other organisms. MSH plays a key role in oxidative stress management and is oxidized to the dimeric mycothiol disulfide (MSSM) in the process. NADPH-dependent mycothiol disulfide reductase (Mtr) helps to maintain an intracellular reducing environment by reducing MSSM back to MSH. Mtr inhibition studies are currently impaired by limited availability of MSSM. Substrate demands are particularly high in time-dependent inhibition assays. Here we report an assay that chemically recycles a mixed disulfide substrate analogue in situ, thereby greatly reducing the substrate quantities needed for such assays. This has enabled the development of a continuous assay where linear reaction rates can be maintained for 40 min or longer using minimal substrate concentrations (5 microM versus a substrate K(m) value of 268 microM). In this manner, substrate requirements are reduced by orders of magnitude. Characterization of a novel time-dependent inhibitor, 2-(5-bromo-2-methoxyphenyl)acrylonitrile, is also demonstrated using these procedures.

Learning in a new cardiac surgical center: an analysis of precursor events.

BACKGROUND: Few studies of learning in the health care sector have analyzed measures of process, as opposed to outcomes. We assessed the learning curve for a new cardiac surgical center using precursor events (incidents or circumstances required for the occurrence of adverse outcomes). METHODS: Intraoperative precursor events were recorded prospectively during major adult cardiac operations, categorized by blinded adjudicators, and counted for each case (overall and according to these categories). Trends in the number of precursor events were analyzed by hospital and by defining 10 equal-sized groups across time, as were trends in outcomes obtained from institutional databases. Results from the first 101 cases performed at a new cardiac surgical site (hospital A) were compared with 2 established centers. RESULTS: A steep reduction in the total number of precursor events over time was observed in the early experience of hospital A (9.2 +/- 4.9 to 2.0 +/- 1.2 events per case, from first to last decile of time, P(trend) < .0001) compared with qualitatively stable levels in the other hospitals; this reduction was driven largely by decreases in the minor severity (P(trend) < .0001), compensated (P(trend) < .0001), and environment (P(trend) < .0001) categories of precursor events. No detectable changes over time were observed in postoperative mortality and complications. No significant improvement was observed in patient comorbid conditions or medical status over time to explain the trend in hospital A. CONCLUSION: Analyzing and targeting specific kinds of process-related failures (precursor events) may provide a novel and sensitive means of tracking, deconstructing, and optimizing organizational learning in medicine.

Impact of cardiac intraoperative precursor events on adverse outcomes.

BACKGROUND: Although extensive study has been directed at the influence of patient factors and comorbidities on cardiac surgical outcomes, less attention has been focused on process. We sought to examine the relationship between intraoperative precursor events (those events that precede and are requisite for the occurrence of an adverse event) and adverse outcomes themselves. METHODS: Anonymous, prospectively collected intraoperative data was merged with database outcomes for 450 patients undergoing major adult cardiac operations. Precursor events were categorized by type, person most affected, severity, and compensation. Number and categories of precursor events were analyzed as predictors of a composite outcome combining death or near miss complications (DNM), using logistic regression. RESULTS: Precursor events occurred more frequently in cases with a DNM outcome than in those with no adverse event (2.7 +/- 2.4 vs 2.0 +/- 2.3/procedure, P = .005). After adjustment for other patient characteristics, the number of precursor events remained an independent predictor of DNM (RR, 1.14 per event [1.04 to 1.24]). Of 990 events, 35.6% related to management, 28.8% were technical, and 22.8% were environment-related. The surgeon was most affected in 40.8%, and 16.5% were of major severity. When categories of precursor events were analyzed, major severity events and those most affecting the surgeon were independent predictors of DNM. CONCLUSIONS: More detailed study of process in complex operations may lead to improved quality of care and patient safety. Special attention must be paid particularly to high risk patients and high risk precursor events.

Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation.

Several studies have suggested that a potential mechanism for estrogen-mediated neuroprotection following experimental stroke is a result of modulating glutamate-mediated excitotoxicity. Our laboratory has shown that in male rats, estrogen injection (systemic or direct intracortical injection) resulted in an immediate depolarization of cortical neurons. Therefore, the present study was designed to investigate whether the estrogen-induced depolarization of cortical neurons was required in mediating the early events associated with this neuroprotection. We tested this hypothesis by co-injecting selective antagonists of the NMDA (MK-801) or AMPA (DNQX) glutamatergic receptors with estrogen. Systemic injection of estrogen significantly attenuated the MK-801-induced decrease in infarct volume following middle cerebral artery occlusion (MCAO). Similarly, when estrogen and MK-801 were co-injected directly into the cortex, no neuroprotection was observed. However, when estrogen or MK-801 was injected centrally 10 min prior to the injection of the other drug, significant neuroprotection was observed. This led us to hypothesize that estrogen-mediated neuroprotection required an initial activation of NMDA receptors. Furthermore, our results suggest that this estrogen-mediated neuroprotection was also associated with a significant increase in m-calpain and activation of an endoplasmic reticulum (ER) specific caspase-12. Finally, the results of current clamp experiments showed that estrogen significantly depolarized cortical neurons as well as enhanced NMDA-induced depolarization. Taken together, these results suggest that estrogen pretreatment may activate NMDA receptors resulting in modification of ER-associated molecular mechanisms involved in neuroprotection following MCAO.

Prospective assessment of intraoperative precursor events during cardiac surgery.

OBJECTIVE: Increasing attention has been afforded to the ubiquity of medical error and associated adverse events in medicine. There remains little data on the frequency and nature of precursor events in cardiac surgery, and we sought to characterize this. METHODS: Detailed, anonymous information regarding intraoperative precursor events (which may result in adverse events) was collected prospectively from six key members of the operating team during 464 major adult cardiac surgical cases at three hospitals and were analyzed with univariable statistical methods. RESULTS: During 464 cardiac surgical procedures, 1627 reports of problematic precursor events were collected for an average of 3.5 and maximum of 26 per procedure. 73.3% of cases had at least one recorded event. One-third (33.3%) of events occurred prior to the first incision, and 31.2% of events occurred while on bypass. While 68.0% of events were regarded as minor in severity (e.g., delays and missing equipment), a substantial proportion (32.0%) was considered major and included anastomotic problems, pump failure, and drug errors. Most problems (90.4%) were reported as being compensated for, although many (30.9%) were never discussed among the team. Major events were more likely to be discussed (p<0.0001) and less likely to have been previously encountered (p=0.0005). Perceptions of the severity and compensation of events varied across the team, as did temporal patterns of reporting (p<0.0001). CONCLUSIONS: A wide range of problematic precursor events occurs during the majority of cardiac surgery procedures. Attention to causes and ways of preventing these precursor events could have an impact on the rate of significant errors and improve the safety of cardiac surgery.

Mesenchymal stem cells induce apoptosis of activated T cells.

Mesenchymal stem cells (MSC) have recently been used successfully in humans to control severe graft-versus-host disease. However, the mechanisms involved in their immunomodulatory effects remain a matter of debate. Here, we show that MSC are unable to activate allogeneic T cells even in the presence of T-cell growth factors. We then found that MSC inhibit T-cell proliferation triggered either by allogeneic, mitogenic or antigen-specific stimuli. Interestingly, MSC inhibit T-cell proliferation by inducing apoptosis of activated T cells, but have no effect on resting T cells. Furthermore, we show that this apoptosis could be related to the conversion of tryptophan into kynurenine by indoleamine 2,3-dioxygenase expressed by MSC in the presence of IFNgamma. Moreover, we show that the inhibitory effect of MSC is neither abrogated nor modified during expansion in culture or after irradiation. Together, these results bring new insight to the mechanisms of immunosuppression induced by MSC and might help to develop their clinical use controlling immune-related adverse effects in humans.

Protection of insulin-secreting INS-1 cells against oxidative stress through adenoviral-mediated glutathione peroxidase overexpression.

OBJECTIVES: A large fraction of an islet graft can be lost early following allotransplantation from various non specific mechanisms including oxidative stress. Overexpression of antioxidant enzymes could confer a beneficial effect on islets exposed to reactive oxygen and nitrogen species. We examined the viability of beta cells driven to overexpress glutathione peroxidase (GPx) and exposed to a superoxide donor (hypoxanthine/xanthine oxidase HX/XO) and a nitric oxide donor (3-morpholinosydnonimine SIN-1). METHODS: Cultured INS-1 rat-derived insulin-secreting cells were transfected by an E1-deleted adenovirus carrying GPx cDNA (AdGPx). Additional experiments were performed with an adenovector carrying Cu/Zn superoxide dismutase cDNA (AdSOD). Cellular viability was tested by the WST-1 colorimetric assay and functionality by static incubation. RESULTS: AdGPx increased GPx activity within 48 hours from 0 (untransfected cells) to 60 +/- 11 U/g (cells transfected at an MOI of 25: 1). GPx overexpression significantly reduced cytotoxicity induced by HX/XO from 10.81 +/- 1.41 to 5.42 +/- 2.62% at 10 mU/ml and from 61.19 +/- 4.17 to 52.9 +/- 4.39% at 20 mU/ml (p=0.0002, transfected cells vs control cells). Doses of SIN-1 from 600 to 1000 micromol/l resulted in cytotoxicity ranging from 17.66 +/- 3.48 to 45.97 +/- 6.48% in control cells and from 5.65 +/- 1.37 to 35.80 +/- 5.59% in AdGPx transfected cells (p=0.015). The combination of AdGPx and AdSOD did not exhibit any synergistic cytoprotective effect. Control cells exposed to a HX/XO stress exhibited a reduction in glucose-theophylline stimulated insulin secretion by half, while stressed GPx overexpressing-cells maintained the same insulin secretion level than non-stressed cells. CONCLUSIONS: Adenoviral-induced overexpression of GPx enhances the resistance of a rat beta cell line to both reactive oxygen (ROS) and reactive nitrogen species (RNS) cytotoxicity. Transposition of these findings to human islet transplantation with a clinically-relevant procedure deserves further investigations.

Hospital disclosure practices: results of a national survey.

New patient safety standards from JCAHO that require hospitals to disclose to patients all unexpected outcomes of care took effect 1 July 2001. In an early 2002 survey of risk managers at a nationally representative sample of hospitals, the vast majority reported that their hospital's practice was to disclose harm at least some of the time, although only one-third of hospitals actually had board-approved policies in place. More than half of respondents reported that they would always disclose a death or serious injury, but when presented with actual clinical scenarios, respondents were much less likely to disclose preventable harms than to disclose nonpreventable harms of comparable severity. Reluctance to disclose preventable harms was twice as likely to occur at hospitals having major concerns about the malpractice implications of disclosure.

The effect of decreasing length of stay on discharge destination and readmission after coronary bypass operation.

BACKGROUND: Over the decade of the 1990s, hospital stay after operation declined in response to prospective payment and managed care. As a result, complications previously detected and treated in the hospital may have begun to occur after discharge. In addition, discharge to nursing homes and rehabilitation hospitals may have increased. To address these questions, we used a statewide database to look at the use of postacute care and the 30-day readmission and mortality after coronary bypass operation. METHODS: A modification of the Commonwealth of Massachusetts Division of Health Care Finance and Policy discharge data to include a unique patient identifier allowed us to retrospectively track patient destination at discharge and study 30-day readmission to all hospitals in the state. RESULTS: Over the 3-year period after the institution of the unique patient identifier (1993 to 1996), postoperative length of stay after coronary bypass operation decreased from 7.4 to 6 days (19%, P <.0005), but the 30-day readmission rate (17.7%) did not increase. Discharge to rehabilitation hospitals and skilled nursing facilities rose significantly (11.7% to 23.8%), especially in the Medicare population (17.2% to 38.5%). Mortality in the 30 days after discharge remained constant at 0.3%. CONCLUSIONS: A shorter postoperative length of stay did not appear to disadvantage coronary artery bypass patients by increasing their likelihood of readmission or death. Cost savings from reduced length of stay were offset by increased use of postacute services.

Cytotoxicity in ciprofloxacin-treated human fibroblast cells and protection by vitamin E.

Quinolones (Qs) were shown to have cytotoxic effects in various cell lines including human carcinoma cells; however, mechanism of these effects was not fully understood. To investigate the possibility of the involvement of an oxidative stress induction in this mechanism of action, we examined viability of human fibroblast cells exposed to a Q antibiotic, ciprofloxacin (CPFX), and measured lipid peroxidation and total glutathione (GSH) levels, and activities of catalase (Cat), superoxide dismutases (SODs), glutathione peroxidase (GPx). The effects of vitamin E pretreatment on those parameters were also examined. Our results showed that the effect of CPFX on the viability of the cells, as determined by neutral red uptake assay, was time dependent. Cytotoxicity was not observed in the concentration range of 0.0129-0.387 mM CPFX when the cells were incubated for 24 hours. However, significant level of cytotoxicity was observed at concentrations 0.129 and 0.194 mM, and >0.129 mM, following 48 and 72 hours of exposure, respectively. When the cells were exposed to 0.194 mM CPFX for 48 hours, the level of lipid peroxidation increased and the content of total GSH decreased significantly; activities of total SOD, Mn SOD and CuZn SOD did not change; the decrease observed in the activity of Cat was not significant; and the activity of GPx was highly variable. Vitamin E pretreatment of the cells provided significant protection against CPFX-induced cytotoxicity; lowered the level of lipid peroxidation significantly, but increased the total GSH content only moderately; no change was observed in the activities of Cat and total SOD, but a significant increase in Mn SOD and a significant decrease in CuZn SOD were noticed. These results suggested that CPFX-induced cytotoxicity on human fibroblast cell cultures is related to oxidative stress, and vitamin E pretreatment can afford a protection.