Salvage therapy for multidrug-resistant tuberculosis

AbstractTreatment of multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to both isoniazid and rifampicin, is challenging under the best of circumstances, and particularly in resource-limited settings. For patients who remain persistently sputum-culture-positive despite therapy with second-line TB drugs, treatment options are limited, especially if disease is too advanced for resective surgery. Salvage therapy refers to the design of a regimen combining new and previously used drugs in a final effort to attain sputum conversion before declaring treatment to have failed. We retrospectively evaluated the outcomes of salvage therapy in 213 Peruvian patients. Salvage regimens included a median of two new drugs (range 1–6) and nine (range 5–13) total (new plus previously used) drugs. The most frequently used new drug was moxifloxacin, followed by capreomycin, amoxicillin-clavulanate, kanamycin and clarithromycin. Culture conversion occurred in 65 (30.5%) patients. Salvage regimens that included moxifloxacin were significantly more likely to be followed by culture conversion (OR 2.2; p 0.02). Later-generation fluoroquinolones such as moxifloxacin should be used in salvage therapy but also in the initial treatment of MDR-TB, if the best clinical strategy is to use the most effective drugs when the patient has the best chance for cure. New TB drugs are most likely to be initially used in salvage patients, in conditions similar to those described here. Close bacteriological monitoring of these patients will be essential, as useful information about the best way to use these new drugs can be gained from analysis of salvage therapy cohorts

Boundary critical behavior at m-axial Lifshitz points for a boundary plane parallel to the modulation axes

The critical behavior of semi-infinite $d$-dimensional systems with $n$-component order parameter $\bm{\phi}$ and short-range interactions is investigated at an $m$-axial bulk Lifshitz point whose wave-vector instability is isotropic in an $m$-dimensional subspace of $\mathbb{R}^d$. The associated $m$ modulation axes are presumed to be parallel to the surface, where $0\le m\le d-1$. An appropriate semi-infinite $|\bm{\phi}|^4$ model representing the corresponding universality classes of surface critical behavior is introduced. It is shown that the usual O(n) symmetric boundary term $\propto \bm{\phi}^2$ of the Hamiltonian must be supplemented by one of the form $\mathring{\lambda} \sum_{\alpha=1}^m(\partial\bm{\phi}/\partial x_\alpha)^2$ involving a dimensionless (renormalized) coupling constant $\lambda$. The implied boundary conditions are given, and the general form of the field-theoretic renormalization of the model below the upper critical dimension $d^*(m)=4+{m}/{2}$ is clarified. Fixed points describing the ordinary, special, and extraordinary transitions are identified and shown to be located at a nontrivial value $\lambda^*$ if $\epsilon\equiv d^*(m)-d>0$. The surface critical exponents of the ordinary transition are determined to second order in $\epsilon$. Extrapolations of these $\epsilon$ expansions yield values of these exponents for $d=3$ in good agreement with recent Monte Carlo results for the case of a uniaxial ($m=1$) Lifshitz point. The scaling dimension of the surface energy density is shown to be given exactly by $d+m (\theta-1)$, where $\theta=\nu_{l4}/\nu_{l2}$ is the anisotropy exponent.Comment: revtex4, 31 pages with eps-files for figures, uses texdraw to generate some graphs; to appear in PRB; v2: some references and additional remarks added, labeling in figure 1 and some typos correcte

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete

Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on Ti6Al4V-ELI scaffolds for bone regeneration in an osteoporotic bone environment

The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca-10(PO4)(5.6)(SRO4)(0.4)(OH)(1.6) following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone.MINECO (MAT2015-64831-R, MAT2016-75611-R AEI/FEDER, UE y BI02015-66266-R) Institute de Salud Carlos III (RD12-0019-0032) European Research Council (Advanced Grant VERDI; ERC-2015-AdG Proposal 694160

Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on Ti6Al4V-ELI scaffolds for bone regeneration in an osteoporotic bone environment.

The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone. STATEMENT OF SIGNIFICANCE Reconstruction of bones after severe trauma or tumors extirpation is one of the most challenging tasks in the field of orthopedic surgery. This scenario is even more complicated in the case of osteoporotic patients, since their bone regeneration capability is decreased. In this work we present a porous implant that promotes bone regeneration even in osteoporotic bone. By coating the implant with an osteogenic bioceramics such as silicon substituted hydroxyapatite and subsequent adsorption of vascular endothelial growth factor, these implants stimulate the bone ingrowth when they are implanted in osteoporotic sheep

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Epidemiology of surgery associated acute kidney injury (EPIS-AKI) : a prospective international observational multi-center clinical study

The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear. We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay. We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration. In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Performance of reconstruction and identification of τ leptons decaying to hadrons and vτ in pp collisions at √s=13 TeV

The algorithm developed by the CMS Collaboration to reconstruct and identify τ leptons produced in proton-proton collisions at √s=7 and 8 TeV, via their decays to hadrons and a neutrino, has been significantly improved. The changes include a revised reconstruction of π⁰ candidates, and improvements in multivariate discriminants to separate τ leptons from jets and electrons. The algorithm is extended to reconstruct τ leptons in highly Lorentz-boosted pair production, and in the high-level trigger. The performance of the algorithm is studied using proton-proton collisions recorded during 2016 at √s=13 TeV, corresponding to an integrated luminosity of 35.9 fb¯¹. The performance is evaluated in terms of the efficiency for a genuine τ lepton to pass the identification criteria and of the probabilities for jets, electrons, and muons to be misidentified as τ leptons. The results are found to be very close to those expected from Monte Carlo simulation