Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion–positive non–small cell lung cancer

Carcinoma; Càncer de pulmó de cèl·lules no petites; Seguretat del pacientCarcinoma; Cáncer de pulmón de células no pequeñas; Seguridad del pacienteCarcinoma; Non–small cell lung cancer; Patient safetyBackground Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion–positive non–small cell lung cancer (NSCLC). Research design and methods Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs. Results In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. Conclusions GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes.The paper received funding from Takeda Development Center Americas Inc., Lexington, MA, USA

Central Public Administration: Working Conditions and Industrial Relations - Ireland

[Excerpt] The political system in Ireland is highly centralised, with the vast majority of political and governing power vested in Dáil Éireann (lower house of parliament) and more particularly in the cabinet and the Taoiseach (prime minister). Ireland has what Pollitt and Bouckaert (2004) would call a unitary political system, with the upper house of parliament (Seanad Éireann) and the president having little influence, and the cabinet wielding huge influence over the legislation that is brought before the Dáil. The total number of people employed in the public sector grew from around 317,000 in 2001 to 360,000 in 2008, a growth of 14%. Excluding commercial state-sponsored bodies, the numbers employed in the public service grew from 270,000 in 2000 to 320,000 in 2008, a growth of 19%. Since the financial recession, however, there has been a significant drop in the numbers employed in both the public sector and public service from 2008, with a drop of just under 6% in each case. Numbers employed in the public sector and public service in 2011 were just below 2007 levels of employment. Growth in public service numbers from 2001 to 2008 was primarily concentrated in the health and education sectors. Two out of every three people employed in the public service work in either health or education. Numbers employed in the civil service, by contrast, have remained relatively stable over the period 2001 to 2011, increasing slightly from 36,100 to 36,600. Numbers rose slightly from 2001 to 2008, when there were 39,300 people employed in the civil service, but have declined since then. The civil service is not large by European standards. An OECD (2010) study comparing eight countries (Canada, Denmark, Finland, Ireland, the Netherlands, New Zealand, Sweden and the UK) showed that Ireland had the third lowest general government employment per 1,000 population (67) in 2006, which was significantly behind Denmark (137), Sweden (125) and Finland (99). A subsequent OECD (2011) study showed that in 2008 in Ireland, employment in general government as a percentage of the labour force (14.8%) was around the OECD average. In 2010, the OECD undertook a survey of the compensation of central government employees (OECD, 2011). This included not only salaries and wages, but also social benefits and future pension earnings. On average, top managers’ (top public servants below the minister) total compensation in responding countries amounts to just under USD 230,000 (€168,212 as at 17 October 2013) PPP.1 At just under USD 290,000 (€212,159) PPP, the compensation of top managers in Ireland is towards the higher end of the European countries surveyed. For the next level down from the top senior managers, a reduced sample of OECD countries shows compensation levels in Ireland to be close to the OECD average, at USD 184,000 (€134,552) PPP. The survey also examined the compensation of middle managers (defined as those responsible for planning, directing and coordinating the general functioning of a specific administrative unit within a government department or ministry). The average compensation for the European countries surveyed is just under USD 140,000 (€102,390) PPP. Compensation in Ireland for this group is USD 155,000 (€113,350) PPP, a little above the European average. Secretaries’ (defined as general office clerks who perform a range of clerical and administrative tasks) compensation was also examined. In general, the level of compensation varies less across countries than it does for the management positions. Compensation in Ireland for secretaries was found to be somewhat below the average of the European countries surveyed, assessed at USD 44,000 (€32,175) PPP, compared with the European average of USD 49,000 (€35,830) PPP

PPP-Completeness with Connections to Cryptography

Polynomial Pigeonhole Principle (PPP) is an important subclass of TFNP with profound connections to the complexity of the fundamental cryptographic primitives: collision-resistant hash functions and one-way permutations. In contrast to most of the other subclasses of TFNP, no complete problem is known for PPP. Our work identifies the first PPP-complete problem without any circuit or Turing Machine given explicitly in the input, and thus we answer a longstanding open question from [Papadimitriou1994]. Specifically, we show that constrained-SIS (cSIS), a generalized version of the well-known Short Integer Solution problem (SIS) from lattice-based cryptography, is PPP-complete. In order to give intuition behind our reduction for constrained-SIS, we identify another PPP-complete problem with a circuit in the input but closely related to lattice problems. We call this problem BLICHFELDT and it is the computational problem associated with Blichfeldt's fundamental theorem in the theory of lattices. Building on the inherent connection of PPP with collision-resistant hash functions, we use our completeness result to construct the first natural hash function family that captures the hardness of all collision-resistant hash functions in a worst-case sense, i.e. it is natural and universal in the worst-case. The close resemblance of our hash function family with SIS, leads us to the first candidate collision-resistant hash function that is both natural and universal in an average-case sense. Finally, our results enrich our understanding of the connections between PPP, lattice problems and other concrete cryptographic assumptions, such as the discrete logarithm problem over general groups

Impact of foot progression angle modification on plantar loading in individuals with diabetes mellitus and peripheral neuropathy

AIMS: To determine if participants can reduce foot progression angle (FPA), and if FPA reduction decreases regional plantar stresses and forces in individuals with diabetes. METHODS: DESIGN: Three-group cross-sectional design with repeated measures. SUBJECTS: twenty-eight participants either with diabetes mellitus (DM), diabetes and peripheral neuropathy with (DMPN+NPU) or without a prior history of ulceration (DMPN−NPU) were studied. INTERVENTION: Participants were first instructed to walk over a 3.6 m walkway at their preferred FPA, and then to walk with their foot aligned parallel with the line of gait progression at their self-selected speed. Dynamic plantar kinetics in six masked regions were collected using an EMED-st-P-2 pedobarograph. MAIN MEASURES: Primary outcome measures were FPA, peak plantar pressure (PPP), and force-time integral (FTI). A repeated measures ANOVA was conducted to determine group differences in FPA for both walking conditions. Regional differences in PPPs and FTIs between preferred and corrected walking conditions were analyzed using repeated measures ANCOVA. RESULTS: Participants showed a reduction in FPA magnitude on the ‘Involved’ foot between the preferred and corrected walking conditions (p<0.01). There were no differences in PPPs or FTIs in any mask between walking conditions (p>0.05). CONCLUSION: Results from this investigation offer important evidence that people with diabetes can modify their FPA with a simple intervention of visual and verbal cueing. Future research should examine if gait retraining strategies in regular footwear more effectively offload areas of elevated regional plantar stresses and forces in adults with diabetes mellitus and peripheral neuropathy

The value of mortality risk reductions in Delhi, India

The authors interviewed commuters in Delhi, India, asking them to report their willingness to pay (WTP) to reduce their risk of dying in road traffic accidents in each of three scenarios that mirror the circumstances under which the majority of the road fatalities in Delhi occur. The WTP responses are internally valid, in the sense that WTP increases with the size of the risk reduction, income, and exposure to road traffic risks, as measured by length of commute and whether the respondent drives a two-wheeler. As a result, the"value of a statistical life"(VSL) is individuated-that is, it varies across groups of beneficiaries. For the most likely beneficiaries of road safety programs-the most highly exposed individuals-the VSL is about 150,000 PPP$.Transport Economics Policy&Planning,Roads&Highways,Airports and Air Services,Road Safety,Insurance&Risk Mitigation

The Value of Mortality Risk Reductions in Delhi, India

We interviewed commuters in Delhi, India, to estimate their willingness to pay (WTP) to reduce their risk of dying in road traffic accidents in three scenarios that mirror the circumstances under which traffic fatalities occur in Delhi. The WTP responses are internally valid: WTP increases with the size of the risk reduction, income, and exposure to road traffic risks, as measured by length of commute and whether the respondent drives a motorcycle. As a result, the value of a statistical life (VSL) varies across groups of beneficiaries. For the most highly exposed individuals, the VSL is about 150,000 Purchasing Power Parity (PPP) dollars.Health and Safety