Using mechanistic models to highlight research priorities for tick-borne zoonotic diseases: Improving our understanding of the ecology and maintenance of Kyasanur Forest Disease in India.

The risk of spillover of zoonotic diseases to humans is changing in response to multiple environmental and societal drivers, particularly in tropical regions where the burden of neglected zoonotic diseases is highest and land use change and forest conversion is occurring most rapidly. Neglected zoonotic diseases can have significant impacts on poor and marginalised populations in low-resource settings but ultimately receive less attention and funding for research and interventions. As such, effective control measures and interventions are often hindered by a limited ecological evidence base, which results in a limited understanding of epidemiologically relevant hosts or vectors and the processes that contribute to the maintenance of pathogens and spillover to humans. Here, we develop a generalisable next generation matrix modelling framework to better understand the transmission processes and hosts that have the greatest contribution to the maintenance of tick-borne diseases with the aim of improving the ecological evidence base and framing future research priorities for tick-borne diseases. Using this model we explore the relative contribution of different host groups and transmission routes to the maintenance of a neglected zoonotic tick-borne disease, Kyasanur Forest Disease Virus (KFD), in multiple habitat types. The results highlight the potential importance of transovarial transmission and small mammals and birds in maintaining this disease. This contradicts previous hypotheses that primates play an important role influencing the distribution of infected ticks. There is also a suggestion that risk could vary across different habitat types but currently more research is needed to evaluate this relationship. In light of these results, we outline the key knowledge gaps for this system and future research priorities that could inform effective interventions and control measures.

Pharmaceutical treatment of osteoarthritis.

OBJECTIVE: To review the current state of pharmaceutical treatment recommendations for the management of osteoarthritis. METHOD: A narrative review was drafted to describe treatment guidelines, mechanism of action, pharmacokinetics, and toxicity for nine classes of pharmaceuticals: 1) oral nonsteroidal anti-inflammatory drugs (NSAIDs), 2) topical NSAIDs, 3) COX-2 inhibitors, 4) duloxetine, 5) intra-articular corticosteroids, 6) intra-articular hyaluronic acid, 7) acetaminophen (paracetamol), 8) tramadol, and 9) capsaicin. RESULTS: In general, oral and topical NSAIDs, including COX-2 inhibitors, are strongly recommended first-line treatments for osteoarthritis due to their ability to improve pain and function but are associated with increased risks in patients with certain comorbidities (e.g., heightened cardiovascular risks). Intra-articular corticosteroid injections are generally recommended for osteoarthritis management and have relatively minor adverse effects. Other treatments, such as capsaicin, tramadol, and acetaminophen, are more controversial, and many updated guidelines offer differing recommendations. CONCLUSION: The pharmaceutical management of osteoarthritis is a constantly evolving field. Promising treatments are emerging, and medicines that were once considered conventional (e.g., acetaminophen) are gradually becoming less acceptable based on concerns with efficacy and safety. Clinicians need to consider the latest evidence and recommendations to make an informed decision with their patients about how to optimize treatment plans for patients with knee, hip, polyarticular, or hand osteoarthritis.

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.

Lessons from England's health care workforce redesign: no quick fixes.

In 2000 the English National Health Service (NHS) began a series of workforce redesign initiatives that increased the number of doctors and nurses serving patients, expanded existing staff roles and developed new ones, redistributed health care work, and invested in teamwork. The English workforce redesign experience offers important lessons for US policy makers. Redesigning the health care workforce is not a quick fix to control costs or improve the quality of care. A poorly planned redesign can even result in increased costs and decreased quality. Changes in skill mix and role definitions should be preceded by a detailed analysis and redesign of the work performed by health care professionals. New roles and responsibilities must be clearly defined in advance, and teamwork models that include factors common in successful redesigns such as leadership, shared objectives, and training should be promoted. The focus should be on retraining current staff instead of hiring new workers. Finally, any workforce redesign must overcome opposition from professional bodies, individual practitioners, and regulators. England's experience suggests that progress is possible if workforce redesigns are planned carefully and implemented with skill.

Studies of circulating microparticle release in peripheral blood after pancreatic islet transplantation.

The loss of graft function after intraportal islet transplantation is likely multifactorial involving allogeneic rejection, recurrent autoimmunity, graft exhaustion due to a marginally implanted islet mass, immunosuppressant toxicity, and impaired ß-cell regeneration. Because early markers of the loss of ß-cell mass or function are lacking, monitoring of islet function remains a challenging issue. We have reported herein monitoring of membrane procoagulant microparticles (MPs) as markers of cell stress in the plasma of three recipients with various clinical histories. Early kinetics of C-peptide and MPs followed identical patterns during the first weeks after transplantation; a major increase probably reflected processes related to cell infusion and islet engraftment. Importantly in the case of rejection, MPs and C-peptide showed opposite patterns. A fall in C-peptide was associated with enhanced insulin needs. Our results suggested that a peak in MP levels might indicate rejection with prognotic value. Treatment of the loss of islet function by a new islet infusion or steroid therapy returned MP and C-peptide levels to their baselines with concomitant restoration of islet function. In the patient with suspected acute cellular rejection, MPs also appeared to be sensors of immunosuppressive steroid therapy.

[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.

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.

[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.

Managing the new primary care: the new skills that will be needed.

Developing new models of primary care will demand a level of managerial expertise that few of today's primary care physicians possess. Yet medical schools continue to focus on the basic sciences, to the exclusion of such managerial topics as running effective teams. The approach to executing reform appears to assume that practice managers and entrepreneurs can undertake the managerial work of transforming primary care, while physicians stick with practicing medicine. This essay argues that physicians currently in practice could be equipped over time with the management skills necessary to develop and implement new models of primary care.

[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.

Restructuring within an academic health center to support quality and safety: the development of the Center for Quality and Safety at the Massachusetts General Hospital.

Recent focus on the need to improve the quality and safety of health care has created new challenges for academic health centers (AHCs). Whereas previously quality was largely assumed, today it is increasingly quantifiable and requires organized systems for improvement. Traditional structures and cultures within AHCs, although well suited to the tripartite missions of teaching, research, and clinical care, are not easily adaptable to the tasks of measuring, reporting, and improving quality. Here, the authors use a case study of Massachusetts General Hospital's efforts to restructure quality and safety to illustrate the value of beginning with a focus on organizational culture, using a systematic process of engaging clinical leadership, developing an organizational framework dependent on proven business principles, leveraging focus events, and maintaining executive dedication to execution of the initiative. The case provides a generalizable example for AHCs of how applying explicit management design can foster robust organizational change with relatively modest incremental financial resources.

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.