One sentence summary: Bench to bedside translation using iPSC to characterise phenotype and pharmacology in primary erythromelalgia, an inherited chronic pain condition. ABSTRACTIn common with other chronic pain conditions, inherited erythromelalgia (IEM) represents a significant unmet medical need. The peripherally expressed SCN9A encoded sodium channel Nav1.7 plays a critical role in IEM with gain-of-function leading to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. In five carefully phenotyped IEM patients, a novel highly potent and selective Nav1.7 blocker reduced heat-induced pain in the majority of subjects. In four of the five subjects we used induced pluripotent stem cell (iPSC) technology to create sensory neurons which uniquely emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the iPSC-derived sensory neuron hyperexcitability we saw a trend towards a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, this translational approach is likely to have broader utility to a wide range of pain and sensory conditions. This emphasizes the use of iPSC approaches to bridge between clinical and preclinical studies, enabling greater understanding of a disease and the response to a therapeutic agent in defined patient populations.

The effect of PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker on pain due to diabetic peripheral neuropathy was investigated in a randomised, placebo and active-controlled parallel group clinical trial (NCT02215252). A 1-week placebo-run in the period was followed by a 4-week treatment period and a 1-week placebo run-out/taper-down period. Single-blind placebo was administered throughout run-in and run-out periods. Subjects were randomised to receive either PF-05089771 150 mg twice daily, pregabalin 150 mg twice daily, or placebo during the 4-week treatment period. One hundred thirty-five subjects were randomised. The primary endpoint was the average pain score derived from subjects' Numerical Rating Scale scores over the past 7 days of week 4 of the double-blind treatment period. Predefined efficacy criteria for the trial were the effect of PF-05089771 being >0.5 units better than placebo at interim analysis after completion of the first part of the study. Although a trend for a reduction in the weekly average pain score in the PF-05089771 treatment group was observed, this was not statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.41 (90% credible interval: -1.00 to 0.17). The effect of PF-05089771 was smaller than that seen with pregabalin, which was statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.53 (90% credible interval: -0.91 to -0.20). As predefined efficacy criteria were not met, the study did not proceed to the second part. PF-05089771 was well tolerated. Possible reasons for the modest efficacy observed with PF-05089771 are discussed.

Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Na v 1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A, the gene encoding Na v 1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12-13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin'T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores (P = 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain between attacks (P = 0.001). Hospital Anxiety and Depression Scale scores for five subjects were below the threshold for mild anxiety or depression and none of the 13 subjects were severely anxious and/or depressed. Quantitative sensory testing revealed significantly increased detection thresholds for cold and warm stimuli at affected, compared to unaffected sites. By contrast, significantly decreased cold and heat pain thresholds were found at unaffected sites. Sensory profiles varied considerably between affected and unaffected sites, suggesting the existence of small fibre neuropathy in symptomatic sites. This in-depth clinical characterization of a well-defined inherited erythromelalgia population indicates the importance of characterizing the pain phenotype in individuals before undertaking clinical trials, given the inherent variability of pain both between and within inherited erythromelalgia subjects, even those within a family who carry the same mutation.

The study examines the impact of key determinants of profitability of power and energy sector in Pakistan such as firm size, firm age, firm growth, productivity, financial leverage and electricity crisis discussed in the broader inter-disciplinary literature. For this purpose panel data of 16 firms of power and energy sector is taken for 2001 to 2012. The study considers profitability determinants at the firm as well as industry affiliation levels in examining hypotheses developed from resource-based approaches. Random effect model is used to detect the combination of variables that best estimated the impact of the explanatory variables on the dependent variable. The empirical results suggest that firm size, firm growth, and electricity crisis positively impact the profitability. However, firm age, financial leverage and productivity negatively influence the firm profitability. This study also propose that during the electricity crisis the profitability of power sector is increased even production of this sector is very low. The findings further indicate that larger and younger firms with high growth and low productivity are more likely to be profitable. This study has found that firm productivity and firm size are the strongest determinants of profitability in power and energy sector of Pakistan.

Background: The irrational use, “over the counter supply”, and unregulated supply chains of antimicrobials are contributing toward antimicrobial resistance. Antimicrobial stewardship programs regulate antimicrobials usage to prevent resistance and reduce health care burden. Objective: To assess the knowledge and practice of pharmacists’ working in various healthcare settings toward antimicrobial stewardship in Pakistan. Method: A cross-sectional study was conducted among pharmacists working in different sectors between March to June 2017. Results: A total of 181 pharmacists participated, of whom (n = 145, 80.1%) were males. The majority of participants were in the 20–30 age group (n = 147, 81.2%) and hold Doctor of Pharmacy degrees. More than 80% of pharmacists agreed that “antimicrobial stewardship is essential to improve patient care”; while (n = 159, 87.8%) pharmacists agreed that “pharmacist should be trained on the use of antimicrobial”. Close to 90% of pharmacists agreed that “adequate training should be provided to pharmacists on antimicrobial use”. Regarding the practice of antimicrobial stewardship, (n = 72, 39.8%) pharmacists often/always “make efforts to prevent or reduce the transmission of infections within the community”; (n = 58, 32%) pharmacists never “dispense antimicrobials without a prescription”; and (n = 60, 32%) pharmacist often/always “communicate with prescribers if unsure about the appropriateness of an antibiotic prescription”. Conclusions: Increased antimicrobial stewardship efforts can both optimize the treatment of infections and reduce adverse events associated with antibiotic use. Pharmacists in Pakistan have good knowledge and adopt positive practices toward antimicrobial stewardship. Pharmacist and other health care professionals should collaborate within multi-disciplinary teams to reduce the problem of antimicrobial resistance and improve the quality of life of patients.

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This paper examines the heterogeneous links between board gender diversity and corporate social performance in different industries across China. OLS regression models are approximated using the data of Chinese industries from 2009 to 2015. Robustness test and two-stage least square (2SLS) methods are incorporated to cater for robustness and endogeneity. Board gender diversity (BGD) stimulates corporate social performance (CSP) of firms with environmental and social risk exposure regardless of critical mass and directors’ independence. It does so for firms with governance risk exposure while incorporating the critical mass effect and the director’s independence. Overall, the positive effect of BGD is prevalent in different industries at an aggregate level while considering firms with an overall ESG risk exposure. The findings imply that BGD can mitigate the ESG risk exposure in terms of enhancing the CSP and the advantage can be transpired with the inclusion of even one female director (independent or executive) to the board. The study also highlights that BGD enhances CSP in industries with more environmental and social risk exposure while doing so in industries with governance risk exposure after complementation by critical mass and independent director effects.

Naproxen effectively reduces pain-related brain responses involving different regions and the attenuation is related to subjective pain changes. Our current work yields further support to the utility of fMRI to objectify the acute analgesic effects of a single naproxen dose in patients affected by knee OA. The trial was registered at the EuropeanClinicalTrials Database, "EudraCT Number 2008-004501-33".