Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in the US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. AA acknowledges personal funding from the UK Medical Research Council and Chief Scientist Office of the Scottish Government Health Directorates

The private military industry and neoliberal imperialism: Mapping the terrain

Despite the international reach, and increasing global importance, of the free market provision of military and security services—which we label the Private Security Industry (PSI)—management and organization studies has yet to pay significant attention to this industry. Taking up Grey’s (2009) call for scholarship at the boundaries between security studies and organization studies and building on Banerjee’s (2008) treatment of the PSI as a key element in necrocapitalism, in this article we aim to trace the long history of the PSI and argue that it has re-emerged over the last two decades against, and as a result of, a very specific politico-economic backdrop. We then suggest that the PSI operates as a mechanism for neoliberal imperialism; demonstrate its substitution for and supplementing of the state; and count some of the costs of this privatization of war. Finally, we take seriously Hughes’s (2007) thesis of the growth of a new security-industrial complex, and of the intersecting elites who benefit from this phenomenon

Collapse of a giant iceberg in a dynamic Southern Ocean marine ecosystem: In situ observations of A-68A at South Georgia

Large icebergs (>20 km long) are responsible for most of the freshwater discharged into the Southern Ocean. We report on in situ and satellite observations made during the break-up phase around South Georgia of the giant tabular iceberg A-68A. The in situ measurements were obtained during a 4-day visit by a research vessel in February 2021, where physical, chemical and biological measurements were made at a range of distances away from the main and subsidiary icebergs. These results were compared to a far-field station 133 km away. Up�stream of the iceberg field, water column structure was similar to ambient water although there was evidence of iceberg-associated phytoplankton as a likely remnant of the passage of the icebergs. Nevertheless, enhancement of primary productivity along the path of the icebergs was not resolved in either in situ or monthly mean satellite observations. There was a considerable brash-ice field moving ahead of the icebergs which limited the number of downstream sampling stations. One downstream station within 2 km of iceberg A-68P showed several ice-melt influenced features that distinguished it from most other stations. Firstly, there was a strong stratified meltwater influenced layer that reached to around 120 m. This had the effect of deepening underlying water masses, with the core of the temperature minimum layer around 50 m deeper than elsewhere. Secondly, there was evidence of rapid downward displacement of both particulate material and certain phytoplankton taxa that may be a further result of this water mass deepening. Thirdly, macronutrient profiles were altered, with concentrations of nitrate, silicic acid and phosphate characteristic of deeper layers being found closer to the surface and a dilution of the ambient nutrient pool just above the iceberg draft that we ascribe to meltwater released from basal melting. Meanwhile, nutrient recycling processes associated with organic matter remineralisation were also modified by the physical restructuring of the water column and biotic components. Finally, the ice-associated phytoplankton taxa Pseudo-nitszchia/Nitszchia, found in both upstream and downstream locations, were abundant at this < 2 km-distant station through melting out from the iceberg and subsequent rapid growth. Overall, we resolved alterations to water column structure, nutrient profiles and phytoplankton community composition at fine to medium scales around the iceberg field. Nevertheless, although there may have been longer term and larger scale impacts, the dynamic oceanographic environment, including the presence of a strong oceanographic front and shelf-edge processes, dominated during the collapse of A-68A

Monoclonal gammopathy of undetermined significance and bone health outcomes: a systematic review and exploratory meta-analysis

Monoclonal gammopathy of undetermined significance (MGUS) is a common condition in the elderly. A number of studies have investigated the relationship between MGUS and bone health outcomes including bone mineral density (BMD), osteoporosis and fractures, but no meta-analysis exists. We conducted a systematic review and exploratory meta-analysis comparing bone health outcomes in patients with MGUS. Two independent authors searched PubMed and Scopus from inception until 19 October 2016. A meta-analysis of cross-sectional and longitudinal studies investigating fractures and BMD was conducted. Standardised mean differences (SMD) ± 95% confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. Of 174 initial hits, 10 studies of moderate methodological quality were eligible, including 8711 individuals with MGUS vs. 52,865 controls. Compared to controls, subjects with MGUS showed significantly lower values for radial cortical volumetric BMD (1 study; SMD = -5.45, 95% CI: -7.24 to -3.66), but not at the lumbar spine, femoral neck or hip. The incidence of fractures was higher in people with MGUS (n = 7466) vs. controls (n = 52,304) (RR = 1.36, 95% CI 1.28-1.44, I 2 = 0%) over a median of 12.5-year follow-up. The incidence of vertebral fractures was particularly elevated (RR = 2.50, 95% CI 1.53-4.06) although limited to two studies. In conclusion, although with limitations, our preliminary meta-analysis suggests that patients with MGUS are at higher risk of fractures despite evidence for differences in BMD being equivocal. Future longitudinal research is required to confirm our findings and determine if fracture prevention interventions are warranted in people with MGUS

The Role of For-Profit Actors in Implementing Targeted Sanctions:The Case of the European Union

The evolution of sanctions from comprehensive to targeted has favored the inclusion of for-profit actors in the policy process. Sanctions are used to deal with security challenges and while the role of for-profit actors in the provision of public goods has been investigated, less has been said about their role in the provision of security. This chapter investigates the role of for-profit actors in the implementation of sanctions. More specifically, this chapter suggests a typology of regulatory environments that facilitates explaining and understanding the behavior of for-profit actors in implementing targeted sanctions. By looking at the quality of instructions provided by state authorities and their capacity to monitor the implementation of such decisions, the chapter argues that overcompliance, uneven and lack of compliance are more likely in certain regulatory environments rather than in others. The theoretical framework is tested on the case study of the restrictive measures of the EU. The data for this research was collected through semi-opened interviews and focus groups held in Brussels from 2013 to 2015

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates

Background Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. Methods The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. Results Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and three months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. Conclusions If a significant decrease is observed the treatment can continue but if no decrease occurs the clinician should reassess to identify problems with the treatment, mainly low adherence</p

Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial

Securing the Anthropocene? International Policy Experiments in Digital Hacktivism: A Case Study of Jakarta

This article analyses security discourses that are beginning to self-consciously take on board the shift towards the Anthropocene. Firstly, it sets out the developing episteme of the Anthropocene, highlighting the limits of instrumentalist cause-and-effect approaches to security, increasingly becoming displaced by discursive framings of securing as a process, generated through new forms of mediation and agency, capable of grasping inter-relations in a fluid context. This approach is the methodology of hacking: creatively composing and repurposing already existing forms of agency. It elaborates on hacking as a set of experimental practices and imaginaries of securing the Anthropocene, using as a case study the field of digital policy activism with the focus on community empowerment through social-technical assemblages being developed and applied in ‘the City of the Anthropocene’: Jakarta, Indonesia. The article concludes that policy interventions today cannot readily be grasped in modernist frameworks of ‘problem solving’ but should be seen more in terms of evolving and adaptive ‘life hacks’