An optimal statistical testing policy for software reliability demonstration of safety-critical systems

When software reliability demonstration of safety-critical systems by statistical testing is treated as a Test, Analyse and Fix (TAAF) process, an optimal testing policy can be found, which maximises the probability of success of the whole process, over a pre-determined period of time. The optimisation problem is formulated, solved by stochastic dynamic programming, and demonstrated by two numerical examples

Service quality: mind the gap!

The characteristics of service can be somewhat slippery and difficult to pin down, not least of all because any given service can only be seen through the eyes of its recipient. This is emphasised by Peters (1985) who stated that ‘customers perceive service in their own unique, idiosyncratic, emotional, irrational, end-of-the-day, and totally human terms.’ Furthermore, and as is noted by Deming (1986) compared to a customer’s reaction to the quality of manufactured goods a customer’s reaction to service quality is immediate. However, service quality, whatever it may be, and however complex a phenomena it might also be, cannot be ignored since service quality can be a key competitive differentiating factor. The SERVQUAL scale or gaps model as it has become known is a common method of measuring service quality. This paper will review the gaps model 25 years on, and make a critical evaluation and assessment of whether the model is still as appropriate in view of the current service environment being dynamic and much changed

Olfactory sensitivity to changes in environmental Ca2 in the freshwater teleost Carassius auratus: an olfactory role for the Ca2+ -sensing receptor?

Olfactory sensitivity to changes in environmental Ca2+ has been demonstrated in two teleost species; a salmonid (Oncorhynchus nerka) and a marine/estuarine perciform (Sparus aurata). To assess whether this phenomenon is restricted to species that normally experience large fluctuations in external ion concentrations (e.g. moving from sea water to fresh water) or is present in a much wider range of species, we investigated olfactory Ca2+ sensitivity in the goldfish (Carassius auratus), which is a stenohaline, non-migratory freshwater cyprinid. Extracellular recording from the olfactory bulb in vivo by electroencephalogram (EEG) demonstrated that the olfactory system is acutely sensitive to changes in external Ca2+ within the range that this species is likely to encounter in the wild (0.05–3 mmol l–1). The olfactory system responded to increases in external calcium with increasing bulbar activity in a manner that fitted a conventional Hill plot with an apparent EC50 of 0.9±0.3 mmol l–1 (close to both ambient and plasma free [Ca2+]) and an apparent Hill coefficient of 1.1±0.3 (means ± S.E.M., N=6). Thresholds of detection were below 50 mmol l–1. Some olfactory sensitivity to changes in external [Na+] was also recorded, but with a much higher threshold of detection (3.7 mmol l–1). The olfactory system of goldfish was much less sensitive to changes in [Mg2+] and [K+]. Preliminary data suggest that Ca2+ and Mg2+ are detected by the same mechanism, although with a much higher affinity for Ca2+. Olfactory sensitivity to Na+ may warn freshwater fish that they are reaching the limit of their osmotic tolerance when in an estuarine environment. Olfaction of serine, a potent odorant in fish, was not dependent on the presence of external Ca2+ or Na+. Finally, the teleost Ca2+-sensing receptor (Ca-SR) was shown to be highly expressed in a subpopulation of olfactory receptor neurones by both immunocytochemistry and in situ hybridisation. The olfactory sensitivity to Ca2+ (and Mg2+) is therefore likely to be mediated by the Ca-SR. We suggest that olfactory Ca2+ sensitivity is a widespread phenomenon in teleosts and may have an input into the physiological mechanisms regulating internal calcium homeostasis

Complementary currencies for sustainable development in Kenya: the case of the Bangla-Pesa

This paper is a report on the development of a complementary currency system that allows Kenyans in informal settlements to trade goods and services and meets sustainable development objectives. The system in this report, Bangla-Pesa, uses a mutual-credit model through a network of local business, including many whose owners fall under the extreme poverty line. The paper documents the reasons for its creation, how it was launched, the immediate positive benefits upon launch, and some of the difficulties faced. Bangla-Pesa is shown to facilitate exchanges of roughly 50 Euros in value per day among 109 businesses, which should raise living standards in the community primarily through the utilization of excess business capacity. After only a week of circulation – Bangla-Pesa helped community members increase sales an estimated 22% through capacity trading. This system’s implementation and governance model are detailed with the aim of improving upon and replicating the model for future sustainable development programs

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup

Transient protein-protein interface prediction: datasets, features, algorithms, and the RAD-T predictor

BACKGROUND: Transient protein-protein interactions (PPIs), which underly most biological processes, are a prime target for therapeutic development. Immense progress has been made towards computational prediction of PPIs using methods such as protein docking and sequence analysis. However, docking generally requires high resolution structures of both of the binding partners and sequence analysis requires that a significant number of recurrent patterns exist for the identification of a potential binding site. Researchers have turned to machine learning to overcome some of the other methods’ restrictions by generalising interface sites with sets of descriptive features. Best practices for dataset generation, features, and learning algorithms have not yet been identified or agreed upon, and an analysis of the overall efficacy of machine learning based PPI predictors is due, in order to highlight potential areas for improvement. RESULTS: The presence of unknown interaction sites as a result of limited knowledge about protein interactions in the testing set dramatically reduces prediction accuracy. Greater accuracy in labelling the data by enforcing higher interface site rates per domain resulted in an average 44% improvement across multiple machine learning algorithms. A set of 10 biologically unrelated proteins that were consistently predicted on with high accuracy emerged through our analysis. We identify seven features with the most predictive power over multiple datasets and machine learning algorithms. Through our analysis, we created a new predictor, RAD-T, that outperforms existing non-structurally specializing machine learning protein interface predictors, with an average 59% increase in MCC score on a dataset with a high number of interactions. CONCLUSION: Current methods of evaluating machine-learning based PPI predictors tend to undervalue their performance, which may be artificially decreased by the presence of un-identified interaction sites. Changes to predictors’ training sets will be integral to the future progress of interface prediction by machine learning methods. We reveal the need for a larger test set of well studied proteins or domain-specific scoring algorithms to compensate for poor interaction site identification on proteins in general

Factors Affecting the Pharmacokinetics and Pharmacodynamics of PEGylated Liposomal Irinotecan (IHL-305) in Patients with Advanced Solid Tumors

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged \u3c60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes

CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer

Purpose: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. Patients and Methods: Patients with locally advanced or metastatic chemotherapy–refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. Results: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Conclusion: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway

CX-072 (pacmilimab), a Probody® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

Background: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). / Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). / Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). / Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. / Trial registration number: NCT03013491

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

INTRODUCTION: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324). METHODS: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T cells) and CD274 gene expression. RESULTS: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry. CONCLUSIONS: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression