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An AAV5 vector with a functional factor VIII gene was tested in men with hemophilia A. Men receiving the high dose had a factor VIII level above 5 IU per deciliter at 1 year; most had a normal level. Toxic effects were minimal, and bleeding episodes nearly eliminated.

Drawing on previously unavailable archival material, this book argues that Indonesian nationalism rested on Islamic ecumenism heightened by colonial rule and the pilgrimage. The award winning author Laffan contrasts the latter experience with life in Cairo, where some Southeast Asians were drawn to both reformism and nationalism. After demonstrating the close linkage between Cairene ideology and Indonesian nationalism, Laffan shows how developments in the Middle East continued to play a role in shaping Islamic politics in colonial Indonesia.

Objective To assess the efficacy and safety of pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of baseline hypoalbuminaemia) in critically unwell adults with sepsis of any severity. Design Systematic review and meta-analysis of randomised clinical trials, with trial sequential analysis, subgroup, and meta-regression analyses.Data sources PubMed, PubMed Central, Web of Science (includes Medline, Conference Proceedings Citation Index, Data Citation Index, Chinese Science Citation Database, CAB abstracts, Derwent Innovations Index), OvidSP (includes Embase, Ovid Medline, HMIC, PsycINFO, Maternity and Infant Care, Transport Database), Cochrane Library, clinicaltrials.gov, controlled-trials.com, online material, relevant conference proceedings, hand searching of reference lists, and contact with authors as necessary.Eligibility criteria Prospective randomised clinical trials of adults with sepsis of any severity (with or without baseline hypoalbuminaemia) in critical or intensive care who received pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of hypoalbuminaemia) compared with those who received control fluids (crystalloid or colloid), were included if all-cause mortality outcome data were available. No restriction of language, date, publication status, or primary study endpoint was applied.Data extraction Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk of all-cause mortality was calculated using a random effects model accounting for clinical heterogeneity.Primary outcome measure All-cause mortality at final follow-up.Results Eighteen articles reporting on 16 primary clinical trials that included 4190 adults in critical or intensive care with sepsis, severe sepsis, or septic shock. A median of 70.0 g daily of pooled human albumin was received over a median of 3 days by adults with a median age of 60.8 years as part of fluid volume expansion and resuscitation, with or without correction of hypoalbuminaemia. The relative risk of death was similar between albumin groups (that received a median of 175 g in total) and control fluid groups (relative risk 0.94; 95% confidence interval 0.87 to 1.01; P=0.11; I2=0%). Trial sequential analysis corrected the 95% confidence interval for random error (0.85 to 1.02; D2=0%). Eighty eight per cent of the required information size (meta-analysis sample size) of 4894 patients was achieved, and the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin (GRADE quality of evidence was moderate). Evidence of no difference was also found when albumin was compared with crystalloid fluid (relative risk 0.93; 0.86 to 1.01; P=0.07; I2=0%) in 3878 patents (GRADE quality of evidence was high; 79.9% of required information size) or colloid fluids in 299 patients (relative risk 1.04; 0.79 to 1.38; P=0.76; I2=0%) (GRADE quality of evidence was very low; 5.8% of required information size). When studies at high risk of bias were excluded in a predefined subgroup analysis, the finding of no mortality benefit remained, and the cumulative z score was just outside the boundary of futility. Overall, the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses.Conclusions In this analysis, human albumin solutions as part of fluid volume expansion and resuscitation for critically unwell adults with sepsis of any severity (with or without baseline hypoalbuminaemia) were not robustly effective at reducing all-cause mortality. Albumin seems to be safe in this setting, as a signal towards harm was not detected, but this analysis does not support a recommendation for use.

In 15 participants with hemophilia A treated with a single infusion of AAV5 vector containing the factor VIII gene, 7 who received 6×10 13 vector genomes per kilogram had a median factor VIII level of 20 IU per deciliter, and 6 who received 4×10 13 vg per kilogram had a median level of 13 IU per deciliter. Factor VIII levels decreased in years 2 and 3 of follow-up, but the median annualized rate of bleeding events among these 13 participants remained zero.

Fear is ubiquitous but slippery. It has been defined as a purely biological reality, derided as an excuse for cowardice, attacked as a force for social control, and even denigrated as an unnatural condition that has no place in the disenchanted world of enlightened modernity. In these times of institutionalized insecurity and global terror, Facing Fear sheds light on the meaning, diversity, and dynamism of fear in multiple world-historical contexts, and demonstrates how fear universally binds us to particular presents but also to a broad spectrum of memories, stories, and states in the past. From the eighteenth-century Peruvian highlands and the California borderlands to the urban cityscapes of contemporary Russia and India, this book collectively explores the wide range of causes, experiences, and explanations of this protean emotion. The volume contributes to the thriving literature on the history of emotions and destabilizes narratives that have often understood fear in very specific linguistic, cultural, and geographical settings. Rather, by using a comparative, multidisciplinary framework, the book situates fear in more global terms, breaks new ground in the historical and cultural analysis of emotions, and sets out a new agenda for further research. In addition to the editors, the contributors are Alexander Etkind, Lisbeth Haas, Andreas Killen, David Lederer, Melani McAlister, Ronald Schechter, Marla Stone, Ravi Sundaram, and Charles Walker.

Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke. 497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies. Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41-63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7-27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021). These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.

ObjectivesTo assess the experience of people with long-term respiratory conditions regarding the impact of measures to reduce risk of COVID-19.DesignAnalysis of data (n=9515) from the Asthma UK and British Lung Foundation partnership COVID-19 survey collected online between 1 and 8 April 2020.SettingCommunity.Participants9515 people with self-reported long-term respiratory conditions. 81% female, age ranges from ≤17 years to 80 years and above, from all nations of the UK. Long-term respiratory conditions reported included asthma (83%), chronic obstructive pulmonary disease (10%), bronchiectasis (4%), interstitial lung disease (2%) and ‘other’ (<1%) (eg, lung cancer and pulmonary endometriosis).Outcome measuresStudy responses related to impacts on key elements of healthcare, as well as practical, psychological and social consequences related to the COVID-19 pandemic and social distancing measures.Results45% reported disruptions to care, including cancellations of appointments, investigations, pulmonary rehabilitation, treatment and monitoring. Other practical impacts such as difficulty accessing healthcare services for other issues and getting basic necessities such as food were also common. 36% did not use online prescriptions, and 54% had not accessed online inhaler technique videos. Psychosocial impacts including anxiety, loneliness and concerns about personal health and family were prevalent. 81% reported engaging in physical activity. Among the 11% who were smokers, 48% reported they were planning to quit smoking because of COVID-19.ConclusionsCOVID-19 and related social distancing measures are having profound impacts on people with chronic respiratory conditions. Urgent adaptation and signposting of services is required to mitigate the negative health consequences of the COVID-19 response for this group.

Background The COVID-19 pandemic is having profound psychological impacts on populations globally, with increasing levels of stress, anxiety, and depression being reported, especially in people with pre-existing medical conditions who appear to be particularly vulnerable. There are limited data on the specific concerns people have about COVID-19 and what these are based on. Methods The aim of this study was to identify and explore the concerns of people with long-term respiratory conditions in the UK regarding the impact of the COVID-19 pandemic and how these concerns were affecting them. We conducted a thematic analysis of free text responses to the question “What are your main concerns about getting coronavirus?”, which was included in the British Lung Foundation/Asthma UK (BLF-AUK) partnership COVID-19 survey, conducted between the 1st and 8th of April 2020. This was during the 3rd week of the UK’s initial ‘social distancing measures’ which included advice to stay at home and only go outside for specific limited reasons. Results 7039 responses were analysed, with respondents from a wide range of age groups (under 17 to over 80), gender, and all UK nations. Respondents reported having asthma (85%), COPD (9%), bronchiectasis (4%), interstitial lung disease (2%), or ‘other’ lung diseases (e.g. lung cancer) (1%). Four main themes were identified: (1) vulnerability to COVID-19; (2) anticipated experience of contracting COVID-19; (3) pervasive uncertainty; and (4) inadequate national response. Conclusions The COVID-19 pandemic is having profound psychological impacts. The concerns we identified largely reflect contextual factors, as well as their subjective experience of the current situation. Hence, key approaches to reducing these concerns require changes to the reality of their situation, and are likely to include (1) helping people optimise their health, limit risk of infection, and access necessities; (2) minimising the negative experience of disease where possible, (3) providing up-to-date, accurate and consistent information, (4) improving the government and healthcare response.