British Lung Foundation/United Kingdom primary immunodeficiency network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, −0.5, and −1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: “GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded.” There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51)

Relationship between microbiology of throat swab and clinical course among primary care patients with acute cough: a prospective cohort study.

BACKGROUND: Acute lower respiratory tract infections (ALRTIs) account for most antibiotics prescribed in primary care despite lack of efficacy, partly due to clinician uncertainty about aetiology and patient concerns about illness course. Nucleic acid amplification tests could assist antibiotic targeting. METHODS: In this prospective cohort study, 645 patients presenting to primary care with acute cough and suspected ALRTI, provided throat swabs at baseline. These were tested for respiratory pathogens by real-time polymerase chain reaction and classified as having a respiratory virus, bacteria, both or neither. Three hundred fifty-four participants scored the symptoms severity daily for 1 week in a diary (0 = absent to 4 = severe problem). RESULTS: Organisms were identified in 346/645 (53.6%) participants. There were differences in the prevalence of seven symptoms between the organism groups at baseline. Those with a virus alone, and those with both virus and bacteria, had higher average severity scores of all symptoms combined during the week of follow-up than those in whom no organisms were detected [adjusted mean differences 0.204 (95% confidence interval 0.010 to 0.398) and 0.348 (0.098 to 0.598), respectively]. There were no differences in the duration of symptoms rated as moderate or severe between organism groups. CONCLUSIONS: Differences in presenting symptoms and symptoms severity can be identified between patients with viruses and bacteria identified on throat swabs. The magnitude of these differences is unlikely to influence management. Most patients had mild symptoms at 7 days regardless of aetiology, which could inform patients about likely symptom duration

Inherited human group IVA cytosolic phospholipase A(2) deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation

This research was supported by an Imperial College Junior Research Fellowship (to N.S.K.), Wellcome Trust program grant (0852551Z108/Z to J.A.M. and T.D.W.), British Heart Foundation Ph.D. studentship (FS/10/033/28271 to F.R.), British Heart Foundation project grant (PG/11/39/28890 to D.B.-B.), and by the Intramural Research Program of the U.S. National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES025034 to D.C.Z.)

Using liminality to understand mothers’ experiences of long-term breastfeeding: ‘Betwixt and between’, and ‘matter out of place’

© 2015, © The Author(s) 2015. Breastmilk is widely considered as the optimum nutrition source for babies and an important factor in both improving public health and reducing health inequalities. Current international/national policy supports long-term breastfeeding. UK breastfeeding initiation rates are high but rapidly decline, and the numbers breastfeeding in the second year and beyond are unknown. This study used the concept of liminality to explore the experiences of a group of women breastfeeding long-term in the United Kingdom, building on Mahon-Daly and Andrews. Over 80 breastfeeding women were included within the study, which used micro-ethnographic methods (participant observation in breastfeeding support groups, face-to-face interviews and online asynchronous interviews via email). Findings about women’s experiences are congruent with the existing literature, although it is mostly dated and from outside the United Kingdom. Liminality was found to be useful in providing insight into women’s experiences of long-term breastfeeding in relation to both time and place. Understanding women’s experience of breastfeeding beyond current usual norms can be used to inform work with breastfeeding mothers and to encourage more women to breastfeed for longer

Loss of β-III Spectrin Leads to Purkinje Cell Dysfunction Recapitulating the Behavior and Neuropathology of Spinocerebellar Ataxia Type 5 in Humans

Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III(−/−) Purkinje cells while in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4- (protein interactor of β-III spectrin) and subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling

A global perspective on marine photosynthetic picoeukaryote community structure

A central goal in ecology is to understand the factors affecting the temporal dynamics and spatial distribution of microorganisms and the underlying processes causing differences in community structure and composition. However, little is known in this respect for photosynthetic picoeukaryotes (PPEs), algae that are now recognised as major players in marine CO2 fixation. Here, we analysed dot blot hybridisation and cloning–sequencing data, using the plastid-encoded 16S rRNA gene, from seven research cruises that encompassed all four ocean biomes. We provide insights into global abundance, α- and β-diversity distribution and the environmental factors shaping PPE community structure and composition. At the class level, the most commonly encountered PPEs were Prymnesiophyceae and Chrysophyceae. These taxa displayed complementary distribution patterns, with peak abundances of Prymnesiophyceae and Chrysophyceae in waters of high (25:1) or low (12:1) nitrogen:phosphorus (N:P) ratio, respectively. Significant differences in phylogenetic composition of PPEs were demonstrated for higher taxonomic levels between ocean basins, using Unifrac analyses of clone library sequence data. Differences in composition were generally greater between basins (interbasins) than within a basin (intrabasin). These differences were primarily linked to taxonomic variation in the composition of Prymnesiophyceae and Prasinophyceae whereas Chrysophyceae were phylogenetically similar in all libraries. These data provide better knowledge of PPE community structure across the world ocean and are crucial in assessing their evolution and contribution to CO2 fixation, especially in the context of global climate change

The Making of a Productivity Hotspot in the Coastal Ocean

Highly productive hotspots in the ocean often occur where complex physical forcing mechanisms lead to aggregation of primary and secondary producers. Understanding how hotspots persist, however, requires combining knowledge of the spatio-temporal linkages between geomorphology, physical forcing, and biological responses with the physiological requirements and movement of top predators.) off the Baja California peninsula, Mexico.We have identified the set of conditions that lead to a persistent top predator hotspot, which increases our understanding of how highly migratory species exploit productive regions of the ocean. These results will aid in the development of spatially and environmentally explicit management strategies for marine species of conservation concern

The influence of submarine groundwater discharges on subtidal meiofauna assemblages in south Portugal (Algarve)

Submarine groundwater discharges (SGD) have been documented as contributing to the biological productivity of coastal areas, through a bottom-up support to higher trophic levels. Nevertheless, the effects on the bottom levels of the coastal food web, namely the meiofauna, are still very poorly known. The “Olhos de Água” beach is the only area on the South coast of Portugal where submarine freshwater seepages have been identified. In this study, meiofauna assemblages in the area impacted by SGD were compared with the meiofauna from a similar area, but without SGD. Samples were taken in Spring and Summer 2011, under different hydrological regimes, aquifer recharge (after Winter) and dryness (after Spring), respectively. The major changes in the community were recorded at a seasonal level, with higher abundances and number of taxa in Spring, when compared to Summer. This may be explained by better sediment aeration during spring along with higher food availability from the sedimentation of spring phytoplankton blooms. Although no significant differences were detected by multivariate analysis on the meiofauna abundances between Control and Impact areas, pair-wise tests on the interactions between factors in number of taxa (S) and species richness (Margalef's d) suggested that the discharge of groundwater stimulated an increase in meiofauna diversity. Such effect can be observed between the meiofauna assemblages from impacted and control areas and also between periods with different discharge regimes (Spring and Summer) in the impacted area. These findings highlight the role that freshwater discharges from coastal aquifers have on meiofauna assemblages and suggest that SGD contribute to enhance the transfer of energy from the lower levels of the trophic web to upper levels

Endangered right whales enhance primary productivity in the bay of fundy

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Marine mammals have recently been documented as important facilitators of rapid and efficient nutrient recycling in coastal and offshore waters. Whales enhance phytoplankton nutrition by releasing fecal plumes near the surface after feeding and by migrating from highly productive, high-latitude feeding areas to low-latitude nutrient-poor calving areas. In this study, we measured NH4 + and PO4 3- release rates from the feces of North Atlantic right whales (Eubalaena glacialis), a highly endangered baleen whale. Samples for this species were primarily collected by locating aggregations of whales in surface- Active groups (SAGs), which typically consist of a central female surrounded by males competing for sexual activity. When freshly collected feces were incubated in seawater, high initial rates of N release were generally observed, which decreased to near zero within 24 hours of sampling, a pattern that is consistent with the active role of gut microflora on fecal particles. We estimate that at least 10% of particulate N in whale feces becomes available as NH4 + within 24 hours of defecation. Phosphorous was also abundant in fecal samples: Initial release rates of PO4 3- were higher than for NH4 +, yielding low N/P nutrient ratios over the course of our experiments. The rate of PO4 3- release was thus more than sufficient to preclude the possibility that nitrogenous nutrients supplied by whales would lead to phytoplankton production limited by P availability. Phytoplankton growth experiments indicated that NH4 + released from whale feces enhance productivity, as would be expected, with no evidence that fecal metabolites suppress growth. Although North Atlantic right whales are currently rare (approximately 450 individuals), they once numbered about 14,000 and likely played a substantial role in recycling nutrients in areas where they gathered to feed and mate. Even though the NH4 + released from fresh whale fecal material is a small fraction of total whale fecal nitrogen, and recognizing the fact that the additional nitrogen released in whale urine would be difficult to measure in a field study, the results of this study support the idea that the distinctive isotopic signature of the released NH4 + could be used to provide a conservative estimate of the contribution of the whale pump to primary productivity in coastal regions where whales congregate

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.T.C. is supported by National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King’s College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union’s 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the “Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jaci.2016.06.02