Viewpoint: filovirus haemorrhagic fever outbreaks: much ado about nothing?

The recent outbreak of Marburg haemorrhagic fever in the Democratic Republic of Congo has put the filovirus threat back on the international health agenda. This paper gives an overview of Marburg and Ebola outbreaks so far observed and puts them in a public health perspective. Damage on the local level has been devastating at times, but was marginal on the international level despite the considerable media attention these outbreaks received. The potential hazard of outbreaks, however, after export of filovirus from its natural environment into metropolitan areas, is argued to be considerable. Some avenues for future research and intervention are explored. Beyond the obvious need to find the reservoir and study the natural history, public health strategies for a more timely and efficient response are urgently needed

Two-dimensional superconductivity at the (111)LaAlO3_3/SrTiO3_3 interface

We report on the discovery and transport study of the superconducting ground state present at the (111)LaAlO$_3$/SrTiO$_3$ interface. The superconducting transition is consistent with a Berezinskii-Kosterlitz-Thouless transition and its 2D nature is further corroborated by the anisotropy of the critical magnetic field, as calculated by Tinkham. The estimated superconducting layer thickness and coherence length are 10 nm and 60 nm, respectively. The results of this work provide a new platform to clarify the microscopic details of superconductivity at LaAlO$_3$/SrTiO$_3$ interfaces, in particular in what concerns the link with orbital symmetry.Comment: 4 pages, 4 figure

Isotope effects in underdoped cuprate superconductors: a quantum phenomenon

We show that the unusual doping dependence of the isotope effects on transition temperature and zero temperature in - plane penetration depth naturally follows from the doping driven 3D-2D crossover, the 2D quantum superconductor to insulator transition (QSI) in the underdoped limit and the change of the relative doping concentration upon isotope substitution. Close to the QSI transition both, the isotope coefficient of transition temperature and penetration depth approach the coefficient of the relative dopant concentration, and its divergence sets the scale. These predictions are fully consistent with the experimental data and imply that close to the underdoped limit the unusual isotope effect on transition temperature and penetration depth uncovers critical phenomena associated with the quantum superconductor to insulator transition in two dimensions.Comment: 6 pages, 3 figure

Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively

A population-based study describing characteristics, survival and the effect of TKI treatment on patients with EGFR mutated stage IV NSCLC in the Netherlands

INTRODUCTION: Since 2011, treatment guidelines advise targeted therapy (tyrosine kinase inhibitor, TKI) for patients with activating epidermal growth factor receptor (EGFR) mutations (EGFR+) in non-small cell lung cancer (NSCLC). We describe characteristics, first line treatment and survival of patients diagnosed with EGFR+ NSCLC in a European population, focussing on age, gender and trends over time and compare to the whole group and EGFR-. METHODS: All patients with non-squamous NSCLC stage IV, diagnosed 2011-2018, were identified from the population-based Netherlands Cancer Registry (N = 31,291). RESULTS: Among all, 7.0% were registered to be EGFR+, with highest prevalence in females 65 years to 23.6 months in the EGFR+ group <50 years treated with TKI. Over time, OS for the whole group increased by 0.6 months, of which 33% due to TKI treatment in EGFR+. The increase was strongest in females <50 years, where median OS almost doubled to 12.4 months. In the EGFR+, multivariable hazard of death was most strongly associated with the use of TKI (HR 0.45(0.41-0.49)). Of the patients with EGFR+ this space need or not, 71% received TKI treatment. Being young reduced the hazard of death (HR 0.71(95%CI:0.59-0.85)) irrespective of treatment, while male gender increased the hazard of death (HR 1.22(95%CI:1.11-1.33)). CONCLUSION: At population level, TKI treatment in patients with non-squamous NSCLC stage IV EGFR+ has very strong beneficial effects on outcome. Of the improvement in OS that was made over the years for the whole group, about one third seems to be attributed to TKI treatment in EGFR+ patients

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(−/−);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms

Effect of minimal enteral feeding on recovery in a methotrexate-induced gastrointestinal mucositis rat model

Patients suffering from gastrointestinal mucositis often receive parenteral nutrition as nutritional support. However, the absence of enteral nutrition might not be beneficial for the intestine. We aimed to determine the feasibility of minimal enteral feeding (MEF) administration in a methotrexate (MTX)-induced mucositis rat model and thereby determine the effect of MEF on recovery. Male Wistar rats were attached to swivel systems from day 1 to 5 after 45 mg/kg MTX IV injection. The MTX group continued ad libitum feeding, and the MTX + MEF group continued ad libitum feeding and received from day 1 to 5 continuously MEF. MEF consisted of 20 % of their normal caloric intake. We measured body weight, intake, and plasma citrulline. At day 10, the rats were terminated and villus and crypt length were measured. The administration of MEF caused no increased severity of mucositis phenotype, with comparable caloric intake, body weight, and plasma citrulline during mucositis. The recovery of plasma citrulline levels was not different between both groups. At day 7 and 8, the MTX + MEF group gained significantly more weight (p <0.05 and p <0.01, respectively), and at day 8 and 9 the total caloric intake was significantly increased (p <0.01 and p <0.05, respectively) compared to the MTX group. At day 10, the rats from the MTX + MEF group showed a significant increase in jejunal villus length compared to the MTX group (p <0.05). This is the first study in which the feasibility of MEF administration during chemotherapy-induced mucositis was determined. This study indicates that MEF administration is feasible during mucositis and suggests that MEF accelerates recovery after MTX-induced mucositis

Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility:when to start treatment?

STUDY QUESTION Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years? SUMMARY ANSWER If a live birth is considered worth Euro32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above Euro32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF. WHAT IS KNOWN ALREADY IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM. STUDY DESIGN, SIZE, DURATION We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS). PARTICIPANTS/MATERIALS, SETTING, METHODS The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54-64% and the average costs from approximately Euro4000 to Euro9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately Euro31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately Euro20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between Euro20 000 and Euro50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of Euro32 000. When we assume a monetary value per live birth over Euro50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth. LIMITATIONS, REASONS FOR CAUTION Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation. WIDER IMPLICATIONS OF THE FINDINGS EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. TRIAL REGISTRATION NUMBER N/A