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Multinational, technology-intensive companies routinely use globally distributed R&D teams, but COVID-19 represented an additional challenge. Lockdowns and home-office working severely limit human interaction and can impact the communication, social interaction, and knowledge sharing critical to successful R&D. Our study investigated how COVID-19 affected R&D processes at three global companies, using a project complexity perspective. Although R&D managers responsible for global projects are accustomed to the challenges of managing communications, the fact that teams were forced into home-office working made new product development more difficult in several ways. Ensuring that technical details are understood by all members of dispersed teams is crucial. Of particular note, and central to our findings, is the emphasis that R&D managers placed on maintaining a high level of social interaction in their teams, and special efforts were needed to keep interactions at a sufficient level to foster the generation and transfer of tacit knowledge. The findings have strong implications for the way that R&D project management is likely to be conducted in a post-COVID-19 world, and we demonstrate how the complexity framework we used can benefit managers in navigating this and other challenges. European Union funding: 810329 (KEEN)

Purpose The sudden arrival of Covid-19 severely disrupted the supply chain of personal protective equipment (PPE) in Australia. This paper aims to examine the development of a geographical cluster, which, through the application of additive manufacturing (AM), responded to the PPE supply crisis. Design/methodology/approach This longitudinal case study focuses on an AM cluster, which was developed to supply PPE in a responsive and flexible manner from 2019/2020. The study gathered data over three stages of cluster evolution: pre, during and post-peak Covid-19. Findings The type and nature of exchanges between organizations involved in the cluster established important insights into success factors for cluster creation and development. Using an established complexity framework, this study identifies the characteristics of establishing a cluster. The importance of cluster alignment created initially by a common PPE supply goal led to an emerging commercial and relational imperative to address the longer-term configuration after the disruption. Practical implications Clusters can be a viable option for a technology-driven sector when there is a “buzz” that drives and rapidly diffuses knowledge to support cluster formation. This research identifies the structural, socio-political and emergent dimensions, which need to be considered by stakeholders when aiming at improving competitiveness using clusters. Originality/value Covid-19 has rapidly and unexpectedly disrupted the supply chain for many industries. Responding to challenges, businesses will investigate different pathways to improve the overall resilience including on-/near-shoring. The results provide insights into how clusters are formed, grow and develop and the differentiating factors that result in successful impacts of clusters on local economies.

Navigating complexity remains one of the key pragmatic challenges that call for temporal organizing as a response. Whilst project-based organizing is established as an approach integral to deploying temporal organizing we still know little about the lived experiences of project managers as they enact it. It, therefore, merits academic study and attention to analyze further how project-based organizing is practised and why it is practiced in unique ways that offer insights into the practical judgements that underpin project managers’ action choices. We present findings from a study investigating the lived experience of 43 project managers from key sectors in countries around the globe. We use the empirical findings of this qualitative study to show how project managers embody and not only enact the dynamics of temporary organizing in the ways they navigate project complexities and form their judgements on an ongoing basis. This process of practising is marked by leaps of faith that can mark new measures of project success beyond the traditional parameters of project completion on time and budget. This paper makes a compelling case for a new school of thought in advancing temporal organizing that we will call the ‘Practising School’, which informs our understanding of the dynamics of project-based organizing and offers insights into how practitioners navigate the ongoing project complexities inherent in project-based organizing. We pave the way for advancing a practice-based perspective for studying projectification and extend current conceptualizations of temporal organizing.

Purpose Research on the “black box” of cognitive capital remains limited in supply chain resilience (SCRES) literature. Drawing from an in-depth single case study of a major consumer electronics multinational facing the COVID-19 disruption, this paper aims to develop a clearer picture of cognitive capital’s elements while contextualizing how they interact with SCRES temporal capabilities to prepare, respond, recover and learn. Design/methodology/approach Consisting of 40 in-depth interviews collected during a four-month period, this single case revolves around the buyer’s view across 36 multiregional buyer–supplier dyads, spanning 17 product and service categories. Data were processed during the pandemic, while findings discuss pre- and intra-crisis events based on two scenarios: the impact of disruption on category demand, comparing sudden pandemic-driven product and service demand fluctuations (i.e. increase, decrease); and the geographical proximity of the supplier relative to the buying firm. Findings The case unveils different elements of cognitive capital (e.g. shared goals, assumptions, values, kinesics language, multilingualism, virtual negotiation, prior disruption experience, shared process capabilities) during a major global disruption, suggesting that different cognitive capital elements influence positively and differently SCRES’ temporal capabilities. Overall, buying firms are urged to build on cognitive capital to improve SCRES preparation, response, recovery and learning. Originality/value This paper extends the understanding of cognitive capital in buyer–supplier relationships by identifying its elements and offering a theoretical articulation of how they enable episodically the four SCRES temporal capabilities under contingencies of increased and decreased demands, and suppliers’ geographical proximity.

PurposeThe purpose of this paper is to systematically review, synthesize and critically evaluate the current research status on the role of collaborative interorganizational relationships (CIRs) in supply chain risks (SCRs) from a social capital perspective and provide an organizing lens for future scholarship in this area.Design/methodology/approachThis study adopts a systematic literature review approach to investigate 126 articles from 27 peer-reviewed journals between 1995 and 2020.FindingsThis paper investigates supply chain CIRs using a social capital perspective to explain the role of structural, relational and cognitive capital that resides in these relationships in various SCRs (i.e. environmental, supply, manufacturing, demand, information, financial and transportation). The review reveals that the three social capital dimensions uniquely and both positively and negatively affect different SCRs. The findings further suggest that the perceived SCRs can influence the structural and relational capital.Practical implicationsThis study calls for practitioners to consider the cognitive alignment with their supply network partners, their relational investments, as well as the interorganizational processes and systems in managing and alleviating SCRs.Originality/valueThis review offers a theoretical articulation of how various aspects of CIRs affect SCRs. Specifically, this study extends the existing understanding of the role of social capital in SCRs through offering a synthesis of dominant findings and discourses, and avenues for future research.

BACKGROUND AND AIMS Alport Syndrome (AS) is the second most common genetic kidney disease and results from mutations in COL4A3, A4 or A5 genes. It is characterized by glomerulonephritis, CKD, hearing loss, and ocular lens defects. Estimated incidence is ∼ 1 in 50 000 live births with prevalence of 1 in 5000–10 000. About 80% patients reach ESKD by age 35 years. The UK Alport Registry, part of the National Registry of Rare Kidney Diseases (RaDaR), performs on-going collection of longitudinal data of AS patients. The aims of this study were to characterize demographic and lab data of AS patients and determine the proportion of AS patients at risk for rapid kidney function decline. METHOD Eligible patients had a clinical, histological or genetic diagnosis of ‘Alport syndrome’ or ‘thin basement membrane nephropathy’ by their physician and provided informed consent. Some data were entered manually, but most routine test results were collected by automatic link between RaDaR and renal IT systems. eGFR was calculated using CKD-EPI Cr equation without race adjustment (2021) or Schwartz equation for subjects ≤16 years of age at time of Cr measurement. For eGFR slope calculations, a minimum of four measurements over at least 2 years were required to be included in this analysis; subjects were censored if they reached ESKD, defined as maintenance dialysis, transplant, or ≥ 2 consecutive eGFR measurements of RESULTS Between 4 January 2013 and 29 November 2021, 887 patients were recruited. See Table 1 for summary of data stratified by age groups. Overall, 52% male versus 48% female, and in those with genotyping data, 54% had X-linked AS with a mean age of 25.8 years at diagnosis and a mean age of proteinuria onset of 29.6 years. Clinically meaningful Stage 2 CKD was already present at time of diagnosis (mean eGFR 72.7 mL/min/1.73 m2) in many of those ≥ 18 years of age. A total of 43% of this AS cohort have reached ESKD, at a mean age of 32.8 years. While 37% were on ACEi and 20% on ARB medications, only 4% were on dual RAAS blockade therapy. About 50% had documentation of eGFR loss ≥4 mL/min/1.73 m2 per year, 29% had UPCR > 2 g/g, and 50% of those age ≥ 18 years had reached ESKD. The proportion of patients with ≥1 risk factor for rapid progression of kidney failure (defined as eGFR decline ≥ 4 mL/min/1.73 m2 per year, UPCR > 2 g/g, UACR > 1 g/g or male 18–23 yrs with eGFR < 90 mL/min/1.73 m2 based on ATHENA natural history study) was 41%. CONCLUSION Demographic and genetic characteristics of AS patients in the RaDaR registry are generally comparable with previously reported data. Approximately 50% had eGFR decline ≥ 4 mL/min/1.73 m2 per year and 41% of patients had exhibited ≥ 1 risk factor for future rapid progression of kidney disease. Results should be interpreted with caution, however, in light of the considerable amount of missing data in a number of the analyses. On-going data collection in this open cohort should allow for further insights on the natural history over time as well as identify AS patients for potential enrollment into clinical trials.

Background The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1–5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant. Methods and findings MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%–79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%–76%). A number of symptoms were significantly (p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5–45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3–35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5–66.6], p = 0.002; PCS 66.3 [95% CI 66.2–66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9–50.1], p = 0.002; PCS 48.0 [95% CI 47.9–48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation. Conclusions The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD. Protocol registration PROSPERO CRD42020164737.

Major changes are currently underway across new product development (NPD) practice, and a number of new NPD management methods and processes are emerging. Managers are faced with an array of possible process models and methods to choose from, including the formal Stage-Gate method as well as multiple emerging variants of Agile. The claimed benefits of Agile methods make it attractive, but its suitability is uncertain. In safety-critical organizations and environments a well-controlled, waterfall-based project model would likely be expected. In an empirical study of an R&D department in a large organization creating and adapting complex air traffic management systems we investigate the use and effects of Scrum, the leading Agile method. Since project coordination is a social phenomenon, we apply social capital and project complexity as theoretical lenses for evaluating the effects of Scrum. We find that Scrum and social capital provide reciprocal benefits, and that the stakeholders found Scrum to be an effective and valuable way of working, mitigating the effects of complexity.

Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups. peerReviewed

Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author.

Infection may be a primary cause of renal disease (e.g. postinfectious glomerulonephritis) or affect the kidneys on a background of debilitating illnesses and previous medical interventions. Renal disease may arise as a consequence of immune responses to a pathogen, direct invasion by the microorganism, or the effects of infection on the systemic or local circulations. Glomerulonephritis—associated with chronic and acute bacterial infections. Shunt nephritis follows colonization of a ventriculoatrial shunt, most commonly with Staphylococcus epidermidis, leading to constitutional symptoms, an acute inflammatory response, and (most characteristically) a type 1 mesangiocapillary glomerulonephritis. Infective endocarditis and other deep-seated bacterial infections may produce a similar renal picture, but they can mimic vasculitic syndromes and outcome is dependent on the response of the infection to treatment. Interstitial nephritis—bacteria that can cause this include leptospira (Weil’s disease), Rickettsia rickettsii (Rocky Mountain spotted fever), legionella, and mycobacteria. Viral infections include hantaviruses (haemorrhagic fever with renal syndrome and nephropathia epidemica) and, almost exclusively following renal transplantation, cytomegalovirus and polyomavirus hominis type 1 (BK) virus. HIV-associated renal disorders—these include HIV nephropathy, which is a focal segmental glomerulosclerosis of ‘collapsing’ form, occurring almost exclusively in black patients. Other morphologies are more common in other races, but interstitial disease is also common as a manifestation of infection or of drug toxicity. Hepatitis B virus—chronic infection is strongly associated with membranous nephropathy; affected individuals are HBeAg and HBsAg positive, usually with coexistent hepatitis; seroconversion from HBeAg positive to HBeAb positive (naturally or induced by treatment) is associated with remission of the renal lesion. Hepatitis C virus—chronic infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations.

In this paper we examine the complex relationship between accountability and organizational learning through a case study with the UK Royal Air Force (RAF). Accountability is a complex and contradictory construct that has both positive and negative implications for organizational learning. Within the same organization we observed positive effects of accountability in one organizational learning system, and negative effects of accountability in another. This case study adds to the organizational learning and accountability literatures, showing that accountability to hierarchy, rather than preventing learning, can actually promote effective learning, making it more likely that people will report problems quickly and accurately and take follow-up action. This only applies if the learning objectives align with the broader accountability framework, and if reporting on failures will enhance individual reputation. If not, then people will tend to avoid reporting negative events in order to avoid punishment and reputation damage. Accountability to hierarchy is only negative if it conflicts with the learning objectives.

Background and objectives Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease. Design, setting, participants, & measurements This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function. Results There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], −11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, −8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, −17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99), or in the time from complete remission to relapse. Conclusions Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_01_16_CJN06180519.mp3

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.

Purpose The purpose of this paper is to bring together two seemingly disparate bodies of literature – ambidexterity (the ability both to exploit and explore) and mindfulness – to take a fresh perspective on the management of uncertainty. The authors differentiate between “rule-based” and “mindfulness-based” reliability and explore project risk responses in environments characterised by varying degrees of uncertainty. Design/methodology/approach Five case organisations across a range of industries are used to illustrate how uncertainty may be prepared for and suitable responses activated. This also adds to the understanding of the nature of ambidexterity, which has previously been characterised primarily at the organisational level with relatively few studies looking at managerial actions and “switches” between modes. The data consist of initial survey responses to indicate the level of mindfulness under conditions of normality, followed by interviews studying particular incidents and the nature of the responses. Findings Key practices are identified that support high reliability in complex projects, with four managerial modes (“Traditional”, “Just-in-time”, “Infusion”, and “Entrepreneurial”) that emerged from the data. Practical implications The findings offer managers a practical framework to choose between different modes of reliable performance by considering the uncertainty of the environment and whether the primary driver of the work is efficiency or effectiveness. This allows managers to reflect on their own organisations and practices and identify whether their current approach is suitable. Originality/value This work offers new insight into risk responses in complex environments and shows how the mindfulness and ambidexterity literatures may be used as beneficial lenses to increase understanding. Blending these two schools also offers opportunities for future research.

Resilience is clearly a desirable attribute, but characterising it is challenging, especially as it can be understood either as the response to an incident, or its successful avoidance. Individual- and organizational-level resilience are established fields of study, whereas mid-range, managerial-level, evidence of how ‘localised’ resilience (e.g. in the department, work unit or project) is achieved is lacking. We ask the question ‘What do managers do to support resilience?’ We report on a study carried out with senior staff from five major UK-based organizations. From our qualitative data investigating critical incidents and ‘near-misses’, we unpack the key (ongoing) actions that managers undertake, and show that these can be understood as a complex interweaving of exploitative and exploratory activities. We also identify five response archetypes utilised when an incident occurs. We show the simultaneity of multiple enabling and responding arrangements and, in so doing, uncover the ‘messy’ characteristics over time which enable the awareness and containment of potential and realised adversities, i.e. resilience.

Although apolipoprotein L1 (APOL1) is not known to be a direct cause of renal disease, it has emerged as a powerful cofactor in several important conditions. APOL1 gene polymorphisms account for the restriction of HIV-associated collapsing focal segmental glomerulosclerosis (FSGS) to those with African ancestry. In Africa, the disease-predisposing alleles seem to have been selected for because they convey resistance to some strains of trypanosomiasis. The same alleles are associated with increased susceptibility to primary FSGS, and are probably able to fully account for the excess of FSGS in black races. Two high-risk alleles have been labelled G1 and G2. To have increased susceptibility, individuals must usually have two copies, that is, it is recessive, but the gene frequency is high in West and Southern Africa and in those descended from those regions. The same alleles convey susceptibility to other more common renal diseases. Numerically the most significant association is with nephropathy previously attributed to hypertension. Recent evidence suggests that the gene may increase rate of progression in renal disease of various types, including diabetes. The mechanism is not known.

MYH9 encodes one of three heavy chain isoforms for the non-muscle myosin II (NM II) molecule. NM II is involved in cell structure and shape and motility. Myosin II is very widely expressed but MYH9 is highly expressed in podocytes. MYH9 diseases are characterized by various combinations of autosomal dominant progressive, proteinuric renal disease, giant platelets with low platelet counts, progressive sensorineural hearing impairment, granulocyte inclusions, and in some patients also cataracts. Although the eponyms Epstein and Fechtner have been given to MYH9 renal syndromes, there is a spectrum of manifestations of MYH9 diseases that do not correlate perfectly with genotype. They are best described as MYH9-associated renal disease. The occurrence of progressive deafness and renal failure led to this condition being considered an Alport syndrome variant in the past, but phenotype as well as molecular genetics clearly separate the disorders.

The glomerular basement membrane (GBM) is a condensed network of extracellular matrix molecules which provides a scaffold and niche to support the function of the overlying glomerular cells. Within the glomerulus, the GBM separates the fenestrated endothelial cells, which line capillary walls from the epithelial cells or podocytes, which cover the outer aspect of the capillaries. In common with basement membranes throughout the body, the GBM contains core components including collagen IV, laminins, nidogens, and heparan sulphate proteoglycans. However, specific isoforms of these proteins are required to maintain the integrity of the glomerular filtration barrier.Across the spectrum of glomerular disease there is alteration in glomerular extracellular matrix (ECM) and a number of histological patterns are recognized. The GBM can be thickened, expanded, split, and irregular; the mesangial matrix may be expanded and glomerulosclerosis represents a widespread accumulation of ECM proteins associated with loss of glomerular function. Whilst histological patterns may follow a sequence or provide diagnostic clues, there remains limited understanding about the mechanisms of ECM regulation and how this tight control is lost in glomerular disease. Monogenic disorders of the GBM including Alport and Pierson syndromes have highlighted the importance of both collagen IV and laminin isoforms and these observations provide important insights into mechanisms of glomerular disease.

Cyclophosphamide and plasma exchange are the standard of care in rapidly progressive glomerulonephritis or lung haemorrhage caused by antiglomerular basement membrane (anti-GBM) disease, and it is unusual to encounter patients at earlier stages. Steroids are universally used in addition. There is some evidence that plasma exchange may not be a critical part of treatment at an earlier stage. There is no more than anecdotal evidence for other therapies. Slower-onset therapies such as antibodies to B cells are rarely appropriate. If untreated, patients with severe anti-GBM disease will not recover renal function and are at risk of pulmonary haemorrhage. Evidence for the pathogenicity of circulating anti-GBM antibodies provides rationale for removal of circulating antibodies as rapidly as possible, whilst simultaneously inhibiting their synthesis. This was behind the introduction of the combination of plasma exchange with immunosuppressive therapy in mid 1970s, which revolutionized outcomes. Plasmapheresis aims to remove circulating pathogenic antibodies against GBM and possibly other mediators; cyclophosphamide prevents further synthesis of autoantibodies; and steroids act as anti-inflammatory agents to attenuate the glomerular inflammatory response initiated by anti-GBM antibodies. It is clear from experimental models and occasional observations in man that the anti-cell mediated effects of current therapies are important too. Outcomes vary, but in general patient survival is now good, while renal survival remains poor, in many series less than 50% at 1 year. Treatment is toxic and after an early peak in deaths due to pulmonary haemorrhage, secondary infections are the next threat. It may therefore be best not to immunosuppress patients with a very poor renal prognosis who appear to be at low risk of pulmonary haemorrhage. Treatment can usually be curtailed after 3 months without recurrence. ANCA and anti-GBM antibodies occur together in some patients. This is typically an older group which often has features of vasculitis, and the anti-GBM response may often be secondary. Longer treatment as for small vessel vasculitis is usually indicated.

Background and Purpose— The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods— In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results— There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5%; P =0.01), lower Glasgow Coma Scale scores (median, 13 versus 14; P =0.03), larger ICHs (median, 38 versus 11 mL; P P P =0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21; 95% confidence interval, 0.07–0.63; P =0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8%; 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH; log-rank P =0.04). Conclusions— The baseline characteristics and outcome of lobar ICH differ from other locations.

Creating and sustaining competitive advantage demands that firms both exploit knowledge and capabilities efficiently, and explore ways to innovate and respond flexibly. The study of this dual capability, ambidexterity, has become increasingly prevalent as organizations struggle to address rapidly changing environments. This paper draws upon longitudinal case research into a business transformation to study how organizational ambidexterity was achieved and sustained through the complementary use of programs and projects. In particular, a strategic, emergent approach to the management of the transformation program created flexibility, while the projects embedded in the program were managed to ensure the consistent, reliable and efficient delivery of new products, operating changes and key capabilities. In combining, but not conflating, these management approaches the organization responded successfully to discontinuous changes, and out-performed competitors. This paper adds to our knowledge of how ambidexterity works in practice and the use of projects and programs for implementing strategic change.

This paper describes the application of an Operations Strategy (OS) approach to project-based operations (PBOs), defined as low to medium volume and medium to high variety operations. The OS approach has been extensively and beneficially used in high and medium volume operations. By examining the development of OS from its genesis in manufacturing operations, we identify four aspects of the OS approach — strategic intent, focus, fit and resource configuration. These elevate the discussion of how to configure resources to gain competitive advantage from PBOs, to the level of business leaders. The four aspects are then analysed in greater detail, with a view to determining the adaptations required for application in a PBO. The results of this engaged study indicate that the approach delivered significant new insight for the organisation involved in the study. The contributions of this paper are identified for both practice and theory. For practice we demonstrate an alternative to a reliance on standards and process compliance to an opportunity to gain competitive advantage from PBOs. For theory, we have extended OS into PBOs and provide a basis for future theory testing. We conclude that there is a significant opportunity for further practical and theory development through using an OS perspective.

Objectives The aims of this study were to to assess the feasibility of simultaneous testing for the blood-borne viruses (BBV), HIV, hepatitis C (HCV) and hepatitis B (HBV), in the Emergency Department (ED) and ascertain the seroprevalence for these three viruses in this setting. Methods A pilot BBV testing program was undertaken as part of routine clinical care in the ED. All ED attendees aged between 16 and 65 years old who were able to consent were tested over a 55 week period on an opt out basis. Patients with positive test results were linked to clinical services. Interventions aimed at improving testing rates were implemented and evaluated by quality improvement (QI) methodology. Results Of 25,520 age-eligible ED attendees, 6108 (24%) underwent BBV testing; an additional 1160 (4.5%) underwent a standalone HIV test (total of 7268 (28%) individuals).There were 83/7268 (1.1%) non-negative (ie reactive or equivocal) results for HIV and 103/6108 (1.7%) and 32/6108 (0.52%) for anti-HCV IgG and HBsAg, respectively. Of these, 12 (0.17%), 16 (0.26%) and 8 (0.13%) were new reactive tests for HIV, HCV and HBV, respectively, which were able to be confirmed on a second test. Specific QI interventions led to temporary increases in testing rates. Conclusions An opt out BBV testing program in the ED is feasible and effective at finding new cases. However, the testing rate was low at 24%. Although QI interventions led to some improvement in testing rates, further studies are required to identify ways to achieve sustained increases in testing in this setting.

We report a case of propylthiouracil (PTU)-induced double antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody (anti-GBM antibody) disease causing pulmonary-renal syndrome in a 35-year-old Thai woman with 10-year history of PTU treatment for thyrotoxicosis. She developed clinical symptoms of vasculitis upon receiving long-term PTU treatment. Prednisolone treatment and the switching from PTU to methimazole resulted to short-term clinical improvement. Nevertheless following termination of steroid treatment, she developed recurrent pulmonary hemorrhage and rapidly progressive glomerulonephritis. The kidney biopsy showed crescentic glomerulonephritis with linear IgG deposit on the glomerular basement membrane although transbronchial lung biopsy showed no immune deposit along the alveolar basement membrane. Serum testing for p-ANCA was positive and western blot showed positive antibody to the alpha-3 chain of collagen type IV. Both ANCA and anti-GBM antibody may play a role in the development of end organ damage. To facilitate early and specific intervention, clinicians should be aware of the propensity of PTU to cause lupus-like syndromes with renal involvement. In patients with PTU-induced ANCA-associated glomerulonephritis, serum anti-GBM antibody test may be useful in the early diagnosis of double positive antibodies disease and plasmapheresis should be performed without delay.

We develop a framework to analyze the multilevel knowledge requirements of complex, major projects in terms of ambidexterity–-the ability to exploit (refine existing knowledge) and explore (develop new knowledge). This is an important theme within the wider literature, yet practical operationalization methods for managers and researchers are not evident. We demonstrate the ambidexterity view through an illustrative case study of telecommunications delivery for the London 2012 Olympic Games and show how these concepts can be used to create an effective knowledge strategy. We offer a structure for the analysis of knowledge utilization in projects.

There is little guidance in the literature on programme-based learning and knowledge transfer. We framed our research question as ‘What are the mechanisms for, drivers of, and barriers to programme-based learning?’ and investigated both within- and cross-programme learning at multiple levels. Our exploratory qualitative investigation of senior managers (primarily at the Programme Director/Delivery Director level) in a large UK-based telecommunications and network services provider revealed a number of interesting and important insights. Participants interviewed tended to call upon their own tacit knowledge and experience to understand their programmes in the first instance. Knowledge acquisition and sharing was largely through social contacts and peer-to-peer connections rather than the formal processes. Explicit organisational knowledge in this instance served mainly for reference but could be ‘signposted’ by trusted colleagues. Learning effects varied over the lifecycle of the programme and, in the case organisation, the enterprise programme office was not viewed as being conducive to effective learning. The findings have practical implications for understanding within- and cross-programme learning.

The glomerular basement membrane (GBM) is the vital barrier between blood and glomerular filtrate. Diseases that damage it generally cause haematuria initially, but as architecture becomes disordered proteinuria becomes an increasing feature. Inflammatory glomerulonephritis most commonly does this, but genetic abnormalities of GBM components are another important mechanism. Alport's syndrome, a hereditary nephritis associated with deafness, is the second commonest genetic cause of renal failure. Thin basement membrane nephropathy is thought to be the underlying diagnosis in 25% of patients presenting to nephrologists with microscopic haematuria.

OVERVIEW:The business of technology firms depends on the successful delivery of projects. These projects can be complex and, some say, increasingly so. Assessing and proactively managing that complexity can benefit project delivery. Based on a systematic literature review and multistage field research, we sought to understand the nature of different dimensions of complexity and how they affect the development of a project. Working from that research, we generated a complexity assessment tool, which was tested initially with a global technology firm and then with a wider network of large organizations in other sectors. The result is a complexity-based view of project management that enables greater specificity in articulating, assessing, and coping with both generic complexities and particular context-dependent challenges.

PurposeThe purpose of this paper is to present the findings of a doctoral thesis aimed at identifying how project managers orchestrate ambidexterity (the achievement of both exploitation of existing knowledge and exploration of new knowledge) at the level of the project.Design/methodology/approachThe research reported on here initially involved a systematic literature review of the theoretical and empirical work on ambidexterity. This was followed by a two‐stage empirical investigation. The first stage involved a set of interviews with project managers in a global IT‐services firm to identify the nature of ambidexterity in their work using the lens of intellectual capital. The second stage comprised eight case studies of projects to determine the practices by which project‐level ambidexterity could be achieved.FindingsThe research showed that at the working level, project ambidexterity is a more complex concept than the existing high‐level theorisations would suggest. The key findings of the research reported on here were that the resources used to enable ambidexterity (human, social and project capital) were interwoven with one another and also with the processes of exploitation and exploration. Two configurations of ambidexterity (“distributed” and “point”) were identified, together with five managerial practices that underpin the attainment of project‐level ambidexterity. These were investigated using “parallel‐coding” of the data to gain greater insight.Practical implicationsThis identifies the “how” of ambidexterity in project environments, and offers managers a new way of conceptualising their work in terms of exploitation and exploration in their day‐to‐day activities.Originality/valuePrevious empirical studies of ambidexterity have been focused mostly at the organisational level, using primarily quantitative techniques. This qualitative study has revealed the nature of ambidexterity in complex, working project environments.

Determining the performance of a major project is a challenge for both practitioners and scholars. In the context of operational change projects the challenge is exacerbated by the service-intensive nature of the transformation, temporal disconnects between contracting and delivery and lack of appropriate metrics. This paper considers performance from a service delivery perspective. Current measures of performance were noted to be inadequate in practice. The service operations literature provided frameworks which were investigated for their utility and supplemented by qualitative data to generate an enhanced service performance model. This was then tested using a survey and a structural equation model derived. Development of this yielded new classifications but most importantly, provided a more meaningful method for measuring the performance of operational transformation projects. Specifically, it is shown that expectations and perceptions are measured on different scales, and that quality performance is inseparable from other performance aspects. The contributions of this paper are to address an important practical problem but also to contribute to the development of the discussion of performance management in major projects from an OM perspective.

In this paper, we explain how ambidexterity, the simultaneous pursuit of exploration and exploitation, is enabled at the individual level of analysis. Research on ambidexterity has been dominated by theoretical approaches focusing on the organisational level; however, we know little about how ambidexterity is enacted by employees. There is also limited work on the multilevel aspects of individual employee actions, for example, particular roles and specifically the level of seniority of the role. We address these gaps by asking: Which individual actions are undertaken by employees at particular levels of seniority in the organization to enable ambidexterity? In order to answer this question we draw on previous research to construct reliable measures of the individual actions that enable ambidexterity. The hypothesized mediation effect of these individual actions is confirmed on the basis of survey data from 212 employees from a UK-based Professional Service Firm. The findings indicate that senior employees are more likely to use ‘integration’, ‘role expansion’ and ‘tone setting’, whilst employees with specialist knowledge about their clients use ‘gap filling’ to enable ambidexterity. Finally, we draw together these findings with 35 interviews conducted to present the HRM practices which support ambidexterity.

Communities-of-practice (CoPs) have received significant attention within a variety of literatures but we remain largely ignorant of the potential of purposefully-created CoPs in global organisations. In this context, the challenge is likely to be convincing ‘masters’ (Wenger, 1998) on the merits of joining the conversation on practice at a distance, thus making the willingness for exchange a key to the quality and longevity of the community. We posed the question “Why would busy, dispersed, knowledgeable professionals want to join and participate in a deliberately-organised CoP?” Our 2-year collaborative action study allowed us to observe the CoP and its membership at close range. We conclude that autonomy, competence and belonging underscore participation, co-production and diffusion of innovative problem-solving and practice beyond the CoP. The study will inform organisations contemplating similar interventions and also serves as a basis for further investigation and theory building on organized CoPs by the research community.

The literature on ambidexterity is dominated by theoretical development and does not fully explain how ambidexterity is enacted. There is limited focus on the managerial actions in day-to-day operations that enable this important phenomenon. We posit that projects offer an ideal context to investigate the actions that enable ambidexterity since they necessarily combine planning and control (exploitation) with some degree of novelty (exploration). Using extensive data from eight project-based case studies in the Information Technology services sector, we ask the research question, How is project-based ambidexterity enabled? Within this context, we identify two different types of project-based ambidexterity ( distributed and point ambidexterity) and five managerial actions ( buffering, gap-filling, integration, role-expansion and tone-setting) that enable ambidexterity. We investigate the underlying resource utilisation in terms of intellectual capital (namely, human, social and project capital) and show the complexity of their interplay in achieving ambidexterity. Finally, we develop a model that brings these concepts together and identify how the ‘integration’ function is central to, and interwoven with, the other actions.

Objective Radioiodine (RI) is an important therapeutic option in young patients with thyrotoxicosis. We wanted to determine whether RI is being used more frequently in this age group. Design National survey of Great Britain (England, Wales and Scotland). Methods Sixty-one medical physics departments were asked to provide the age and number of patients with thyrotoxicosis Results Forty-three departments (70%), with representation from 21 of the 25 most populous areas of Great Britain, provided data on 69 258 treatments. The number of treatments recorded on patients P Conclusions A rising proportion of patients with thyrotoxicosis receiving RI are in those

Research on ambidexterity has been focused primarily at the organisational level. There is little in the literature detailing ambidexterity in more complex forms of organising. While much is written on the ‘what’ of ambidexterity – its enactment has been shown to be beneficial – there is a gap in our understanding of the underlying mechanisms, architectures and dynamics by which organisations can achieve both exploration and exploitation. In this article, we use the lens of intellectual capital to extend current architectural theory. A case study of a project management office in an IT/IS multinational provides the context in which to qualitatively unpack the underpinning intellectual capital architecture, illustrating the interwoven application of human, social and organisational capital in a complicated organisational setting. We reveal the co-existence and mutual interdependence of multiple intellectual capital and process elements, further explaining the ‘how’ of this increasingly important area of study.