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“[...] mulheres não tem passado”. As palavras da sobrevivente Ruth Klüger (2005) apontam para uma lógica masculina hegemônica que guia o ato de testemunhar: é indecente para mulheres falarem sobre o outrora. Contudo, Klüger (2005), Delbo (2021) e Veil (2021) mostram que também possuem passados sobre a catástrofe (Shoah) e produziram suas memórias, exercem o papel de superstes. Em Paisagens da memória, O alvorecer em Birkenau e Auschwitz e Depois, respectivamente, os relatos dessas sobreviventes de Auschwitz permitem pensar como foi sobreviver aos campos a partir das representações e sensações femininas: sobre as ações de dessubjetivação mortíferas sobre seus corpos-outros; nos entregam uma paisagem crua do cotidiano no Lager, dos atritos, diferenciações e confluências entre prisioneiras políticas e prisioneiras judias. Por fim, os relatos também possibilitam perceber os afetos como construções de espaços de acolhimento para enfrentar o horror.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Goals: We have recently introduced a new class of wearable loop sensors for joint flexion monitoring that overcomes limitations in the state-of-the-art. Our previous studies reported a proof-of-concept on a cylindrical phantom limb, under static scenarios and with a rigid sensor. In this work, we evaluate our sensors, for the first time, on human subjects, under dynamic scenarios, using a flexible textile-based prototype tethered to a network analyzer. An untethered version is also presented and validated on phantoms, aiming towards a fully wearable design. Methods: Three dynamic activities (walking, brisk walking, and full flexion/extension, all performed in place) are used to validate the tethered sensor on ten (10) adults. The untethered sensor is validated upon a cylindrical phantom that is bent manually at random speed. A calibration mechanism is developed to derive the sensor-measured angles. These angles are then compared to gold-standard angles simultaneously captured by a light detection and ranging (LiDAR) depth camera using root mean square error (RMSE) and Pearson's correlation coefficient as metrics. Results: We find excellent correlation (≥ 0.981) to gold-standard angles. The sensor achieves an RMSE of 4.463° ± 1.266° for walking, 5.541° ± 2.082° for brisk walking, 3.657° ± 1.815° for full flexion/extension activities, and 0.670° ± 0.366° for the phantom bending test. Conclusion: The tethered sensor achieves similar to slightly higher RMSE as compared to other wearable flexion sensors on human subjects, while the untethered version achieves excellent RMSE on the phantom model. Concurrently, our sensors are reliable over time and injury-safe, and do not obstruct natural movement. Our results set the ground for future improvements in angular resolution and for realizing fully wearable designs, while maintaining the abovementioned advantages over the state-of-the-art.

O presente trabalho tem como objetivo discutir diferentes modalidades traumáticas na construção da civilização soviética e do “novo” homo sovieticus por meio de quatro testemunhos de gerações variadas: Aleksandr Soljenítsyn (1918-2008), Liudmila Petruchévskaia (1938-?), Svetlana Aleksiévitch (1948-?) e Alex Halberstadt (1970-?). Na pena desses escritores, os “grandes fatos” estão subsumidos nas histórias individuais e coletivas: nos corpos dos zeks, das famílias, das mulheres, dos jovens, das etnias e, por último, na memória comunista daqueles que acreditavam e foram surpreendidos pelo fim, os chamados, pejorativamente, de sovok.

Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration number ISRCTN41647111.

Objective To evaluate the effect of level 1, high observation beds (HOBs) compared with high dependency unit (HDU) and neurosurgical intensive care unit (NICU) admission on service provision, such as cancelled operations, and healthcare costs.Methods A retrospective, observational, single-centre cross-sectional study at a single, large UK neurosurgical centre. All adult patients admitted to neurosurgical HOBs between December 2021 and July 2022 were included. The list of cancelled procedures was collected from 2019 to 2022. To evaluate the impact of admission of eligible patients to HOBs, the total bed days, cost per bed day, number of admissions and cost per admission were obtained for all clinical areas the financial years 2019/2020 and 2021/2022.Results 307 patients were included in the study: 59.7% of HOBs admissions were elective and 37.7% were acute; admissions were for cranial procedures or conservative treatment (64.8%), spinal (32.6%) or other (2.6%). Following admission, 73.3% of patients were stepped down to the ward prior to discharge home. Only seven patients required escalation to level-2 or level-3 care. Overall, 97% of all HOBs patients were discharged home at the end of hospital stay. Occupancy rate was 90.4%.The cost of bed day increased from ward, level 0 (£384), then level 1 (£376), to level 2 (£787–1211) and to level 3 (£1628). From 2019 to 2021, 558 operations had been cancelled, and 140 (37.8%) of 370 were estimated to have been potentially avoided by HOBs admissions due to conflict of scheduling, ward bed capacity and critical care bed capacity. In addition, a minimum total expenditure due to cancelled operations was estimated at £22 923.50 yearly on average.Conclusion This study recognises HOBs growing role in the management of acutely unwell patients in ward-based environments. While recognising the associated challenges, this study highlighted the potential in reducing healthcare costs. Further studies should evaluate the impact and limitations of HOBs on patients’ recovery and outcomes, compared to HDU and NICU.

Gene therapy holds great promise for the treatment of severe diseases, and adeno-associated virus (AAV) vectors have emerged as valuable tools in this field. However, challenges such as immunogenicity and high production costs complicate the commercial viability of AAV-based therapies. To overcome these barriers, improvements in production yield, driven through the availability of robust and sensitive characterization techniques that allow for the monitoring of critical quality attributes to deepen product and process understanding are crucial. Among the main attributes affecting viral production and performance, the ratio between empty and full capsids along with capsid protein stoichiometry are emerging as potential parameters affecting product quality and safety. This study focused on the production of AAV vectors using the baculovirus expression vector system (BEVS) in Sf9 cells and the complete characterization of AAV5 variants using novel liquid chromatography and mass spectrometry techniques (LC-MS) that, up to this point, had only been applied to reference commercially produced virions. When comparing virions produced using ATG, CTG or ACG start codons of the cap gene, we determined that although ACG was the most productive in terms of virus yield, it was also the least effective in transducing mammalian cells. This correlated with a low VP1/VP2 ratio and a higher percentage of empty capsids. Overall, this study provides insights into the impact of translational start codon modifications during rAAV5 production using the BEVS, the associated relationship with capsid packaging, capsid protein stoichiometry and potency. The developed characterization workflow using LC-MS offers a comprehensive and transferable analysis of AAV-based gene therapies, with the potential to aid in process optimization and facilitate the large-scale commercial manufacturing of these promising treatments.

Introduction Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates.Methods and analysis The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study’s aims.Ethics and dissemination Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals.Trial registration number ISRCTN17658526.

Summary: Cytosine methylation within CG dinucleotides (mCG) can be epigenetically inherited over many generations. Such inheritance is thought to be mediated by a semiconservative mechanism that produces binary present/absent methylation patterns. However, we show here that, in Arabidopsis thaliana h1ddm1 mutants, intermediate heterochromatic mCG is stably inherited across many generations and is quantitatively associated with transposon expression. We develop a mathematical model that estimates the rates of semiconservative maintenance failure and de novo methylation at each transposon, demonstrating that mCG can be stably inherited at any level via a dynamic balance of these activities. We find that DRM2—the core methyltransferase of the RNA-directed DNA methylation pathway—catalyzes most of the heterochromatic de novo mCG, with de novo rates orders of magnitude higher than previously thought, whereas chromomethylases make smaller contributions. Our results demonstrate that stable epigenetic inheritance of mCG in plant heterochromatin is enabled by extensive de novo methylation.

Background and Objectives: The Pacific Island Countries face some of the highest rates of Noncommunicable Diseases (NCDs). This study estimates the economic costs of NCDs for each year from 2015 to 2040, focusing on eleven Pacific Island nations.Data and Methods:Two methods were used to estimate the mortality and morbidity costs using a ‘value of lost output’ and ‘cost of illness’ approach respectively. Results: Five results stand out in terms of projected economic costs of NCD mortality and morbidity analyses in the Pacific: (i) The economic burden of NCDs in the Pacific is greater than expected for middle-income countries; (ii) Although cardiovascular disease is the biggest contributor to the mortality burden in the region, diabetes plays a far greater role in the Pacific countries compared to the global average; (iii) The economic burden of NCDs is increasing with time, especially as incomes rise; (iv)The biggest driver of lost output is the potential loss of labor due to early death from NCDs; and (v) The cost of illness due to diabetes is high across the Pacific countries, with highest among the Polynesian countries. Conclusions: NCDs alone can put enormous threat to the small Pacific economies. Targeted interventions to reduce disease prevalence, as outlined in the Pacific NCDs Roadmap, are vital to reduce the long-term costs associated with NCD mortality and morbidity.

Abstract Background Supportive care interventions used to manage chemotherapy‐induced myelosuppression (CIM), including granulocyte colony‐stimulating factors (G‐CSFs), erythropoiesis‐stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. Methods Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive‐stage small cell lung cancer (ES‐SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1–4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. Results The use of G‐CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p

The Victorian Socialists (VicSocialists) are a socialist electoral organisation in Australia which has had some electoral success as a regional fourth party behind the Greens. This article seeks to address what kind of organisation the VicSocialists are, what communicative techniques the organisation employs in assembling a counterpublic or constituency, and what this case study illustrates in terms of the broader formation of counterpublics in the ‘digital age’. This article characterises the VicSocialists as a “macro-sect”, a new organisational form. The macro-sect is something more than a socialist micro-sect and less than a mass party, while optimistically conceiving of itself as a proto-mass party. The macro-sect strategy is distinct from another 21st-century party-form, the digital party. Unlike the digital parties, which tend to fetishise digital media, the VicSocialists treat digital media soberly as just one tool in the formation and mobilisation of counterpublics, a tool with serious limitations. Additionally, digital media is complementary with face-to-face communication (such as doorknocking) in important ways. A study of a parallel US macro-sect, the DSA, similarly found that activists were ambivalent about digital media, yet strongly used it for promotion. This commonality with the DSA suggests the international emergence of a new organisational form, with a distinct communicative strategy for forming counterpublics in the so-called ‘digital age’ – one which necessarily uses digital media, yet does not fetishise it.

Benign multicystic peritoneal mesothelioma (BMPM) is a rare peritoneal tumor diagnosed predominantly in pre-menopausal women. Associated risk factors include endometriosis and pelvic inflammatory disease in women, and prior abdominal surgery in both genders. To date, the pathogenesis of this disease remains controversial with possible etiologies, including a neoplastic versus a reactive process. Given the risk factors, some authors believe that this disease is secondary to a reactive process. However, because some studies describe cases where there is no prior surgical history or inflammatory milieu present, and because of this entity’s predilection for recurrence, some authors believe the origin to be neoplastic. Some genetic and familial associations have also been reported. Malignant transformation is extremely rare, with only two cases reported in the literature, despite the recurrence potential. Like the etiology, the name of this entity is also controversial. Some authors prefer the term “peritoneal inclusion cyst (PCM)” instead of “benign cystic mesothelioma” and argue that the term mesothelioma should only be used when there is evidence of atypia. Most cases of BMPM are discovered incidentally. Others reflect sequela of tumor mass effect. It appears intra-operatively as large, multi-focal, cystic lesions in the peritoneal and pelvic cavity. Diagnosis is achieved through surgical sampling with histopathological examination. Immunobiologically, BMPM exhibits multiple small cystic spaces with flattened lining containing calretinin positive cells without atypical features, mitotic figures, or tissue invasion. Treatment includes cytoreductive surgery. Here we present a case of BMPM in a 60-year-old male – a rare disease in an uncommon patient population.

Abstract Background All health systems struggle to meet health needs within constrained resources. This is especially true for low-income countries. It is critical that they can learn from wider contexts in order to improve their performance. This article examines policy transfer and evidence use linked to it in low- and middle-income settings. The objective was to inform international investments in improved learning across health systems. Methods The article uses a comparative case study design, drawing on case studies conducted in Bangladesh, Burkina Faso, Cambodia, Ethiopia, Georgia, Nepal, Rwanda and Solomon Islands. One or two recent health system reforms were selected in each case and 148 key informants were interviewed in total, using a semi-structured tool focused on different stages of the policy cycle. Interviewees were selected for their engagement in the policy process and represented political, technical, development partner, non-governmental, academic and civil society constituencies. Data analysis used a framework approach, allowing for new themes to be developed inductively, focusing initially on each case and then on patterns across cases. Results The selected policies demonstrated a range of influences of externally imposed, co-produced and home-grown solutions on the development of initial policy ideas. Eventual uptake of policy was strongly driven in most settings by local political economic considerations. Policy development post-adoption demonstrated some strong internal review, monitoring and sharing processes but there is a more contested view of the role of evaluation. In many cases, learning was facilitated by direct personal relationships with local development partner staff. While barriers and facilitators to evidence use included supply and demand factors, the most influential facilitators were incentives and capacity to use evidence. Conclusions These findings emphasise the agency of local actors and the importance of developing national and sub-national institutions for gathering, filtering and sharing evidence. Developing demand for and capacity to use evidence appears more important than augmenting supply of evidence, although specific gaps in supply were identified. The findings also highlight the importance of the local political economy in setting parameters within which evidence is considered and the need for a conceptual framework for health system learning.

Abstract Background Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. Methods RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. Results We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. Conclusion These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.

El objetivo de este artículo es reflexionar sobre la creación de una infraestructura de investigación ética más sólida en relación con la investigación de la salud de la población indígena en Chile. Se expone un marco de investigación ética que apunta a apoyar una relación más equitativa y colaborativa entre académicos y comunidades indígenas, lo que puede conducir a investigaciones más pertinentes y a mayores beneficios para las comunidades de conformidad con los principios de la investigación bioética. Se emplearon experiencias internacionales para informar sobre la forma en que se podría establecer una infraestructura de investigación de la salud de la población indígena en el contexto chileno. Luego, se presenta el desarrollo y la adopción de directrices para la investigación ética de la salud de la población indígena y la orientación hacia la investigación colaborativa y dirigida por la comunidad como mecanismos que pueden ayudar a lograr estos objetivos.

Population aging presents substantial and unique challenges and opportunities to Pacific Island countries. The countries in this region currently have young populations, but the population is rapidly changing. With some of the highest rates of obesity and diabetes in the world, an aging population will—unless urgent action is taken—put additional pressure on all aspects of the health system: leadership and governance; health financing; health workforce, service delivery; drugs and equipment; and information systems. Pacific Island economies face a particular challenge in terms of health financing: government already finances and provides the majority of health services, but most countries have limited fiscal space to expand and deepen health services for growing and aging populations. Most countries cannot rely on a demographic dividend to finance and strengthen their health systems. Increased efficiency, particularly through better targeted primary and secondary prevention of noncommunicable diseases, is a particularly strategic and feasible investment in the Pacific, improving the health and well-being of those who will age and strengthening the effectiveness, efficiency, and affordability of the broader health system.

Craniosynostosis is a group of conditions characterised by the premature fusion of one or more cranial vault sutures. This may lead to abnormal cranial development with severe skull and craniofacial deformities and if the condition is left untreated, other complications such as raised intracranial pressure and cranial growth restriction may be implicated. Craniosynostosis can arise as part of a genetic syndrome, or nonsyndromically where the pathophysiology remains less clear. Occurring in 1 in 2,000 to 2,500 live births, diagnosis is carried out shortly after birth and treatment of craniosynostosis mostly involves surgery varying from less invasive procedures in those patients diagnosed early to single or repeated open calvarial reconstruction in the more complex cases. This article reviews the different types of craniosynostosis with their variable presentations, underlying genetic mutations, associated complications and neuro-psychological outcomes before discussing its management with distinct emphasis on surgical treatment options within a multidisciplinary team.

Background: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. Objectives: To investigate whether or not combining mirtazapine with serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD). Design: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual. Setting: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. Participants: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. Interventions: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. Main outcome measures: The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients’ views and experiences of managing depression and GPs’ views on prescribing a second antidepressant. Results: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference –1.83 points, 95% confidence interval (CI) –3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: –0.85 points, 95% CI –3.12 to 1.43 points; 12 months: 0.17 points, 95% CI –2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). Conclusions: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. Limitations: Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. Future work: Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation. Trial registration: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

El objetivo de este artículo es reflexionar sobre la creación de una infraestructura de investigación ética más sólida en relación con la investigación de la salud de la población indígena en Chile. Se expone un marco de investigación ética que apunta a apoyar una relación más equitativa y colaborativa entre académicos y comunidades indígenas, lo que puede conducir a investigaciones más pertinentes y a mayores beneficios para las comunidades de conformidad con los principios de la investigación bioética. Se emplearon experiencias internacionales para informar sobre la forma en que se podría establecer una infraestructura de investigación de la salud de la población indígena en el contexto chileno. Luego, se presenta el desarrollo y la adopción de directrices para la investigación ética de la salud de la población indígena y la orientación hacia la investigación colaborativa y dirigida por la comunidad como mecanismos que pueden ayudar a lograr estos objetivos.

In the acute management of a trauma patient, airway patency is of utmost importance. The present case describes a male patient who presented with delayed severe upper airway obstruction secondary to massive subcutaneous emphysema following blunt traumatic injury two days previously. Airway compromise is a rarely described but serious complication of subcutaneous emphysema. Current management of subcutaneous emphysema and its association with pneumothorax is summarized. Early decompression of underlying pneumothoraces in patients with significant subcutaneous emphysema should be performed to avoid this rare complication.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

This article argues the neuroplastic effects of contemporary internet use will have critical implications for the U.S. Intelligence Community. Studies have shown the internet and related technologies are fundamentally changing the way people engage information, which in turn has compromised cognitive functioning in a number of important ways. In the analytic segments of intelligence organizations, this phenomenon speaks directly to a—if not the—core occupational function: focused, disciplined thinking. This issue can be expected to be more pronounced among younger and newer analytic cohorts, though it certainly is not an issue reserved for these cohorts alone. While the internet has brought many advances and advantages to the U.S. Intelligence Community, it is incumbent upon intelligence managers to stay aware of emerging threats to analytic process and outputs. In this article, the basic concepts and science of neuroplasticity are introduced, as well as specific findings pertaining to the neuroplastic effects of internet usage. Potential implications for U.S. intelligence organizations are then explored. The article concludes with suggestions for mitigation and future research.

Agricultural intensification is placing tremendous pressure on the soil’s capacity to maintain its functions leading to large-scale ecosystem degradation and loss of productivity in the long term. Therefore, there is an urgent need to find early-indicators of soil health degradation in response to agricultural management. In recent years, major advances in soil meta-genomic and spatial studies on microbial communities and community-level molecular characteristics can now be exploited as ‘biomarker’ indicators of ecosystem processes for monitoring and managing sustainable soil health under global change. However, a continental scale, cross biome approach assessing soil microbial communities and their functional potential is essential to identify the unifying principles governing the susceptibility of soil biodiversity to land conversion is lacking. Herein we conducted a meta-analysis from a dataset generated from 102 peer-reviewed publications as well as unpublished data to explore how properties directly linked to soil nutritional health ( total C and N; C:N ratio), primary productivity (NPP) and microbial diversity and composition (relative abundance of major bacterial phyla determined by next generation sequencing techniques) are affected in response to agricultural management across the main biomes of Earth (arid, continental, temperate and tropical). In our analysis, we found strong statistical trends in the relative abundance of several bacterial phyla in agricultural (e.g. Actinobacteria and Chloroflexi) and natural (Acidobacteria, Proteobacteria, and Cyanobacteria) systems across all regions and these trends correlated well with many soil properties. However, main effects of agriculture on soil properties and productivity were biome-dependent. Our meta-analysis provides evidence on the predictable nature of the microbial community responses to vegetation type. This knowledge can be exploited in future for developing a new set of indicators for primary productivity and soil health.

Abstract Objective: To determine the growth patterns and citation volume of research publications referring to Indigenous health in Australia from 1972 to 2008 compared to seven selected health fields. Methods: Web of Science was used to identify all publications (n=820) referring to the health of Indigenous Australians authored by Australian researchers, 1972 to 2008. Citations for each publication were also captured. Growth was compared with selected health fields as well as with overall Australian research publications. Results: Research publications referring to Indigenous health, while remaining relatively small in number, grew at an average annual rate of 14.1%, compared with 8.2% across all fields of Australian research. The growth rate shown was equal second highest in our seven categories of health and medical research. However, Indigenous publications were cited significantly less than the Australian average. Conclusions: While there has been positive growth in publications referring to Indigenous health, the attention paid to this research through citations remains disappointingly low. Implications: Given that research concentration and impact can be an index of how seriously a nation considers a health problem, the low visibility of Australian research examining Indigenous health does not demonstrate a level of concern commensurate with the gravity of Indigenous health problems. Further investigation for the reasons for lower citations may identify potential intervention strategies.

To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.

HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.

BACKGROUND:Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS:miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION:These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.

Background Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH.Methods We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression.Results 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia.Conclusions In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care.