Efficient quasi-monoenergetic ion beams from laser-driven relativistic plasmas

Table-top laser-plasma ion accelerators have many exciting applications, many of which require ion beams with simultaneous narrow energy spread and high conversion efficiency. However, achieving these requirements has been elusive. Here we report the experimental demonstration of laser-driven ion beams with narrow energy spread and energies up to 18 MeV per nucleon and similar to 5% conversion efficiency (that is 4 J out of 80-J laser). Using computer simulations we identify a self-organizing scheme that reduces the ion energy spread after the laser exits the plasma through persisting self-generated plasma electric (similar to 10(12) V m(-1)) and magnetic (similar to 10(4) T) fields. These results contribute to the development of next generation compact accelerators suitable for many applications such as isochoric heating for ion-fast ignition and producing warm dense matter for basic science

Efficient quasi-monoenergetic ion beams from laser-driven relativistic plasmas

Table-top laser-plasma ion accelerators have many exciting applications, many of which require ion beams with simultaneous narrow energy spread and high conversion efficiency. However, achieving these requirements has been elusive. Here we report the experimental demonstration of laser-driven ion beams with narrow energy spread and energies up to 18 MeV per nucleon and similar to 5% conversion efficiency (that is 4 J out of 80-J laser). Using computer simulations we identify a self-organizing scheme that reduces the ion energy spread after the laser exits the plasma through persisting self-generated plasma electric (similar to 10(12) V m(-1)) and magnetic (similar to 10(4) T) fields. These results contribute to the development of next generation compact accelerators suitable for many applications such as isochoric heating for ion-fast ignition and producing warm dense matter for basic science

Lipid Lowering Therapy: An Era Beyond Statins.

Dyslipidemia, specifically elevated LDL cholesterol levels, causes atherosclerotic cardiovascular disease (ASCVD) and increases the risk of myocardial infarction and stroke. Statins, a class of drugs that exert their effects by inhibiting HMG-CoA reductase, a key enzyme in the synthesis of cholesterol, have been the mainstay of therapy for the primary prevention of cardiovascular disease and lipids reduction. Statins are associated with side effects, most commonly myopathy and myalgias, despite their proven efficacy. This review explores non-statin lipid-lowering therapies and examines recent advances and emerging research. Over the previous decades, several lipid-lowering therapies, both as monotherapy and adjuncts to statin therapy and lipid-targeting gene therapy, have emerged, thus redefining how we treat dyslipidemia. These drugs include Bile acids sequestrants, Fibrates, Nicotinic acid, Ezetimibe, Bempedoic acid, Volanesoren, Evinacumab, and the PCSK 9 Inhibitors Evolocumab and Alirocumab. Emerging gene-based therapy includes Small interfering RNAs, Antisense oligonucleotides, Adeno-associated virus vectors, CRISPR/Cas9 based therapeutics, and Non-coding RNA therapy. Of all these therapies, Bempedoic acid works most like statins by working through a similar pathway to decrease cholesterol levels. However, it is not associated with myopathy. Overall, although statins continue to be the gold standard, non-statin therapies are set to play an increasingly important role in managing dyslipidemia

Bronchiectasis in India:results from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India Registry

BACKGROUND: Bronchiectasis is a common but neglected chronic lung disease. Most epidemiological data are limited to cohorts from Europe and the USA, with few data from low-income and middle-income countries. We therefore aimed to describe the characteristics, severity of disease, microbiology, and treatment of patients with bronchiectasis in India. METHODS: The Indian bronchiectasis registry is a multicentre, prospective, observational cohort study. Adult patients ( 6518 years) with CT-confirmed bronchiectasis were enrolled from 31 centres across India. Patients with bronchiectasis due to cystic fibrosis or traction bronchiectasis associated with another respiratory disorder were excluded. Data were collected at baseline (recruitment) with follow-up visits taking place once per year. Comprehensive clinical data were collected through the European Multicentre Bronchiectasis Audit and Research Collaboration registry platform. Underlying aetiology of bronchiectasis, as well as treatment and risk factors for bronchiectasis were analysed in the Indian bronchiectasis registry. Comparisons of demographics were made with published European and US registries, and quality of care was benchmarked against the 2017 European Respiratory Society guidelines. FINDINGS: From June 1, 2015, to Sept 1, 2017, 2195 patients were enrolled. Marked differences were observed between India, Europe, and the USA. Patients in India were younger (median age 56 years [IQR 41-66] vs the European and US registries; p<0\ub70001]) and more likely to be men (1249 [56\ub79%] of 2195). Previous tuberculosis (780 [35\ub75%] of 2195) was the most frequent underlying cause of bronchiectasis and Pseudomonas aeruginosa was the most common organism in sputum culture (301 [13\ub77%]) in India. Risk factors for exacerbations included being of the male sex (adjusted incidence rate ratio 1\ub717, 95% CI 1\ub703-1\ub732; p=0\ub7015), P aeruginosa infection (1\ub729, 1\ub710-1\ub750; p=0\ub7001), a history of pulmonary tuberculosis (1\ub720, 1\ub707-1\ub734; p=0\ub7002), modified Medical Research Council Dyspnoea score (1\ub732, 1\ub725-1\ub739; p<0\ub70001), daily sputum production (1\ub716, 1\ub703-1\ub730; p=0\ub7013), and radiological severity of disease (1\ub703, 1\ub701-1\ub704; p<0\ub70001). Low adherence to guideline-recommended care was observed; only 388 patients were tested for allergic bronchopulmonary aspergillosis and 82 patients had been tested for immunoglobulins. INTERPRETATION: Patients with bronchiectasis in India have more severe disease and have distinct characteristics from those reported in other countries. This study provides a benchmark to improve quality of care for patients with bronchiectasis in India. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society, and the British Lung Foundation

Stress-induced lipocalin-2 controls dendritic spine formation and neuronal activity in the amygdala.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Behavioural adaptation to psychological stress is dependent on neuronal plasticity and dysfunction at this cellular level may underlie the pathogenesis of affective disorders such as depression and post-traumatic stress disorder. Taking advantage of genome-wide microarray assay, we performed detailed studies of stress-affected transcripts in the amygdala - an area which forms part of the innate fear circuit in mammals. Having previously demonstrated the role of lipocalin-2 (Lcn-2) in promoting stress-induced changes in dendritic spine morphology/function and neuronal excitability in the mouse hippocampus, we show here that the Lcn-2 gene is one of the most highly upregulated transcripts detected by microarray analysis in the amygdala after acute restraint-induced psychological stress. This is associated with increased Lcn-2 protein synthesis, which is found on immunohistochemistry to be predominantly localised to neurons. Stress-naïve Lcn-2(-/-) mice show a higher spine density in the basolateral amygdala and a 2-fold higher rate of neuronal firing rate compared to wild-type mice. Unlike their wild-type counterparts, Lcn-2(-/-) mice did not show an increase in dendritic spine density in response to stress but did show a distinct pattern of spine morphology. Thus, amygdala-specific neuronal responses to Lcn-2 may represent a mechanism for behavioural adaptation to psychological stress.Marie Curie Excellence Grant from the European Commission.Medical Research Council Project GrantCOST Action ECMNe

Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment

BACKGROUND: For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events. METHODS: In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART. FINDINGS: A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar. INTERPRETATION: Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability. TRIAL REGISTRATION: CTRI/2011/12/00226

Assessing the feasibility of integrating ecosystem-based with engineered water resource governance and management for water security in semi-arid landscapes: A case study in the Banas catchment, Rajasthan, India

Much of the developing world and areas of the developed world suffer water vulnerability. Engineering solutions enable technically efficient extraction and diversion of water towards areas of demand but, without rebalancing resource regeneration, can generate multiple adverse ecological and human consequences. The Banas River, Rajasthan (India), has been extensively developed for water diversion, particularly from the Bisalpur Dam from which water is appropriated by powerful urban constituencies dispossessing local people. Coincidentally, abandonment of traditional management, including groundwater recharge practices, is leading to increasingly receding and contaminated groundwater. This creates linked vulnerabilities for rural communities, irrigation schemes, urban users, dependent ecosystems and the multiple ecosystem services that they provide, compounded by climate change and population growth. This paper addresses vulnerabilities created by fragmented policy measures between rural development, urban and irrigation water supply and downstream consequences for people and wildlife. Perpetuating narrowly technocentric approaches to resource exploitation is likely only to compound emerging problems. Alternatively, restoration or innovation of groundwater recharge practices, particularly in the upper catchment, can represent a proven, ecosystem-based approach to resource regeneration with linked beneficial socio-ecological benefits. Hybridising an ecosystem-based approach with engineered methods can simultaneously increase the security of rural livelihoods, piped urban and irrigation supplies, and the vitality of river ecosystems and their services to beneficiaries. A renewed policy focus on local-scale water recharge practices balancing water extraction technologies is consistent with emerging Rajasthani policies, particularly Jal Swavlamban Abhiyan (‘water self-reliance mission’). Policy reform emphasising recharge can contribute to water security and yield socio-economic outcomes through a systemic understanding of how the water system functions, and by connecting goals and budgets across multiple, currently fragmented policy areas. The underpinning principles of this necessary paradigm shift are proven and have wider geographic relevance, though context-specific research is required to underpin robust policy and practical implementation

Impact of Second Primary Malignancy Post–Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P \u3c .001 and HR 5.01, P \u3c .001, respectively) and OS (HR 3.85, P \u3c .001 and HR 8.13, P \u3c .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT