Substitution Between Managers and Subordinates: Evidence from British Football

We use data on British football managers and teams over the 1994-2007 period to study substitution and complementarity between leaders and subordinates. We find for the Premier League (the highest level of competition) that, other things being equal, managers who themselves played at a higher level raise the productivity of less-skilled teams by more than that of highly skilled teams. This is consistent with the hypothesis that one function of a top manager is to communicate to subordinates the skills needed to succeed, since less skilled players have more to learn. We also find that managers with more accumulated professional managing experience raise the productivity of talented players by more than that of less-talented players. This is consistent with the hypothesis that a further function of successful managers in high-performance workplaces is to manage the egos of elite workers. Such a function is likely more important the more accomplished the workers are -- as indicated, in our data, by teams with greater payrolls.Productivity, leadership

Technical note: Facilitating laparoscopic liver biopsy by the use of a single-handed disposable core biopsy needle

Despite the use of advanced radiological investigations, some liver lesions cannot be definitely diagnosed without a biopsy and histological examination. Laparoscopic Tru-Cut biopsy of the liver lesion is the preferred approach to achieve a good sample for histology. The mechanism of a Tru-Cut biopsy needle needs the use of both hands to load and fire the needle. This restricts the ability of the surgeon to direct the needle into the lesion utilising the laparoscopic ultrasound probe. We report a technique of laparoscopic liver biopsy using a disposable core biopsy instrument (BARD (R) disposable core biopsy needle) that can be used single-handedly. The needle can be positioned with laparoscopic graspers in order to reach posterior and superior lesions. This technique can easily be used in conjunction with laparoscopic ultrasound.M. I. Trochsler, Q. Ralph, F. Bridgewater, H. Kanhere, and Guy J. Madder

Universal and wide shear zones in granular bulk flow

We present experiments on slow granular flows in a modified (split-bottomed) Couette geometry in which wide and tunable shear zones are created away from the sidewalls. For increasing layer heights, the zones grow wider (apparently without bound) and evolve towards the inner cylinder according to a simple, particle-independent scaling law. After rescaling, the velocity profiles across the zones fall onto a universal master curve given by an error function. We study the shear zones also inside the material as function of both their local height and the total layer height.Comment: Minor corrections, accepted for PRL (4 pages, 6 figures

Traveling Granular Segregation Patterns in a Long Drum Mixer

Mixtures of granular media often exhibit size segregation along the axis of a partially-filled, horizontal, rotating cylinder. Previous experiments have observed axial bands of segregation that grow from concentration fluctuations and merge in a manner analogous to spinodal decomposition. We have observed that a new dynamical state precedes this effect in certain mixtures: bi-directional traveling waves. By preparing initial conditions, we found that the wave speed decreased with wavelength. Such waves appear to be inconsistent with simple PDE models which are first order in time.Comment: 11 page

A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study

BACKGROUND: Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC. METHODS: Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment. RESULTS: Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem. CONCLUSION: The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010)

Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy

Funnel plots, performance variation and the Myocardial Infarction National Audit Project 2003–2004

BACKGROUND: Clinical governance requires health care professionals to improve standards of care and has resulted in comparison of clinical performance data. The Myocardial Infarction National Audit Project (a UK cardiology dataset) tabulates its performance. However funnel plots are the display method of choice for institutional comparison. We aimed to demonstrate that funnel plots may be derived from MINAP data and allow more meaningful interpretation of data. METHODS: We examined the attainment of National Service Framework standards for all hospitals (n = 230) and all patients (n = 99,133) in the MINAP database between 1(st )April 2003 and 31(st )March 2004. We generated funnel plots (with control limits at 3 sigma) of Door to Needle and Call to Needle thrombolysis times, and the use of aspirin, beta-blockers and statins post myocardial infarction. RESULTS: Only 87,427 patients fulfilled criteria for analysis of the use of secondary prevention drugs and 15,111 patients for analysis by Door to Needle and Call to Needle times (163 hospitals achieved the standards for Door to Needle times and 215 were within or above their control limits). One hundred and sixteen hospitals fell outside the 'within 25%' and 'more than 25%' standards for Call to Needle times, but 28 were below the lower control limits. Sixteen hospitals failed to reach the standards for aspirin usage post AMI and 24 remained below the lower control limits. Thirty hospitals were below the lower CL for beta-blocker usage and 49 outside the standard. Statin use was comparable. CONCLUSION: Funnel plots may be applied to a complex dataset and allow visual comparison of data derived from multiple health-care units. Variation is readily identified permitting units to appraise their practices so that effective quality improvement may take place

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation

Comparative Immunohistochemical Study of Multicystic Dysplastic Kidneys With and Without Obstruction

Etiology of multicystic dysplastic kidney (MCDK) remains unknown. Not all cases are associated with obstruction. We compared by immunohistochemistry 17 cases of MCDK (10 cases with and seven without obstruction) to 17 controls and 20 fetal kidneys. TGF-β was negative in obstructive MCDKs and positive in nonobstructive MCDK. IGF2 was overexpressed in obstructive and underex-pressed in nonobstructive MCDKs. PAX2, BCL-2, and β-catenin were expressed equally in obstructive and nonobstructive dysplasia. TGF-β and IGF2 work by different mechanisms in obstructive and nonobstructive MCDKs, but there are no differences among PAX 2, BCL-2, and β-catenin in obstructive versus nonobstructive dysplasia

Outcomes of the 2019 Novel Coronavirus in patients with or without a history of cancer - a multi-centre North London experience

© The Author(s) 2020. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background Four months after the first known case of the 2019 novel coronavirus disease (COVID-19), on the 11th March 2020, the WHO declared the outbreak a pandemic and acknowledged the potential to overwhelm national healthcare systems. The high prevalence and associated healthcare, social and economic challenges of COVID-19 suggest this pandemic is likely to have a major impact on cancer management, and has been shown to potentially have worse outcomes in this cohort of vulnerable patients (1). This study aims to compare the outcomes of reverse transcriptase polymerase chain reaction (RT-PCR) confirmed COVID-19 positive disease in patients with or without a history of cancer. Method: We retrospectively collected clinical, pathological and radiological characteristics and outcomes of COVID-19 RT-PCR positive cancer patients treated consecutively in four different North London hospitals (cohort A). Outcomes recorded included morbidity, mortality and length of hospital stay. All clinically relevant outcomes were then compared to consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (12th March- 7th April 2020). Results: A total of 52 electronic patient records during the study time period were reviewed. Cohort A (median age 76 years, 56% males) and cohort B (median age 58 years, 62% male) comprised of 26 patients each. With the exclusion of cancer, both had a median of 2 comorbidities. Within cohort A, the most frequent underlying cancer was colorectal (5/26) and prostate cancer (5/26), and 77% of patients in Cohort A had received previous anti-cancer therapy. The most common presenting symptoms were cough and pyrexia in both cohorts. Frequent laboratory findings included lymphopenia, anaemia and elevated CRP in both cohorts, whilst hypokalaemia, hypoalbuminaemia and hypoproteinaemia was predominantly seen amongst patients with cancer. Median duration of admission was 7 days in both cohorts. The mortality rate was the same in both cohorts (23%), with median age of mortality of 80 years. Of cancer patients who died, all were advanced stage, had been treated with palliative intent and had received anti-cancer therapy within 13 days of admission. Conclusion: Old age, late stage of cancer diagnosis and multiple co-morbidities adversely influence the outcome of patients with COVID-19 positive patients. Whilst extra caution is warranted in the administration of anti-cancer therapies pertaining to the risk of immune-suppression, this data does not demonstrate a higher risk to cancer patients compared to their non-cancer counterparts.Peer reviewedFinal Published versio