Cancer treatment-related neuropathic pain:proof of concept study with menthol—a TRPM8 agonist

PURPOSE: Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol. PATIENTS AND METHODS: Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4–6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4–6 weeks. Secondary outcomes included changes in function, mood and skin sensation. RESULTS: Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed. CONCLUSION: This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required

Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems

Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This "network-free" approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of "partial network expansion" into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility. © 2014 Hogg et al

Joy leads to overconfidence, and a simple countermeasure

Overconfidence has been identified as a source of suboptimal decision making in many real-life domains, with often far-reaching consequences. This study identifies a mechanism that can cause overconfidence and demonstrates a simple, effective countermeasure in an incentive-compatible experimental study. We observed that joy induced overconfidence if the reason for joy (an unexpected gift) was u

A Large-Scale, Open-Domain, Mixed-Interface Dialogue-Based ITS for STEM

We present Korbit, a large-scale, open-domain, mixed-interface, dialogue-based intelligent tutoring system (ITS). Korbit uses machine learning, natural language processing and reinforcement learning to provide interactive, personalized learning online. Korbit has been designed to easily scale to thousands of subjects, by automating, standardizing and simplifying the content creation process. Unlike other ITS, a teacher can develop new learning modules for Korbit in a matter of hours. To facilitate learning across a widerange of STEM subjects, Korbit uses a mixed-interface, which includes videos, interactive dialogue-based exercises, question-answering, conceptual diagrams, mathematical exercises and gamification elements. Korbit has been built to scale to millions of students, by utilizing a state-of-the-art cloud-based micro-service architecture. Korbit launched its first course in 2019 on machine learning, and since then over 7,000 students have enrolled. Although Korbit was designed to be open-domain and highly scalable, A/B testing experiments with real-world students demonstrate that both student learning outcomes and student motivation are substantially improved compared to typical online courses

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

Background: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). Methods and Findings: Three population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06–2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03–1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99–1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12–1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression. Conclusion: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care

First-time patellar dislocation with resultant habitual dislocation two years later, which was not demonstrated on plain X-rays halfway: a case report

We present an instructive case of habitual left patellar dislocation in which the patella had appeared odd due to lateral tilt relative to contralateral side, but had been radiologically confirmed to be on the trochlea at 1 year prior to the referral. An 11-year-old girl presented to our hospital 2 years after the left patella had dislocated with a 'giving way' when cutting to the left. Our physical and radiological examinations confirmed that the left patella was laterally tilted in the patellar groove with the knee in extension but was dislocated in flexion beyond 45°. In spite of these findings, she had been untreated at the previous hospital since all plain X-rays, including a skyline patellar view, had failed to demonstrate the dislocation. Consequently, in addition to reconstruction of medial patellofemoral ligament, she had to undergo a lateral retinacular release, which might have been unnecessary if treated earlier. This case illustrates that first-time patellar dislocation can gradually lead to habitual dislocation subsequently, and that cautious physical examinations in regard to patella tracking are essential since radiological examinations do not always reveal the pathophysiology of patellar instability

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Non-Anatomic Proximal Realignment for Recurrent Patellar Dislocation Does Not Sufficiently Prevent Redislocation

Several operative techniques have been described for recurrent patellar dislocation. Clinical results vary depending on the procedure and indication. The present study aimed to evaluate the clinical outcome of Insall’s proximal realignment for recurrent patellar dislocation at mid-term follow-up. Forty-five patients were reviewed with a mean follow-up period of 49 months after having undergone Insall’s procedure. Outcome measures included reports of redislocations, complications, patient-reported outcome scores (Kujala, Tegner activity scale) and subjective assessment. No statistically significant improvements (p < 0.05) in patient-reported outcome measures were noted. Sixteen patients (35%) had poor to fair results using the Kujala score. Subjective assessment revealed that 12 patients (27%) were dissatisfied with the outcome of their surgery and would not undergo the same procedure. Ten patients (22%) had suffered from redislocation at the latest follow-up. In 4 cases (9%), intra-articular knee hematoma occurred which required arthroscopic intervention. The overall mid-term outcome of the present study shows low patient satisfaction. Non-anatomic realignment for recurrent patellar dislocation does not adequately prevent redislocation

Linkage to HIV care, postpartum depression, and HIV-related stigma in newly diagnosed pregnant women living with HIV in Kenya: a longitudinal observational study

BACKGROUND: While studies have suggested that depression and HIV-related stigma may impede access to care, a growing body of literature also suggests that access to HIV care itself may help to decrease internalized HIV-related stigma and symptoms of depression in the general population of persons living with HIV. However, this has not been investigated in postpartum women living with HIV. Furthermore, linkage to care itself may have additional impacts on postpartum depression beyond the effects of antiretroviral therapy. We examined associations between linkage to HIV care, postpartum depression, and internalized stigma in a population with a high risk of depression: newly diagnosed HIV-positive pregnant women. METHODS: In this prospective observational study, data were obtained from 135 HIV-positive women from eight antenatal clinics in the rural Nyanza Province of Kenya at their first antenatal visit (prior to testing HIV-positive for the first time) and subsequently at 6 weeks after giving birth. RESULTS: At 6 weeks postpartum, women who had not linked to HIV care after testing positive at their first antenatal visit had higher levels of depression and internalized stigma, compared to women who had linked to care. Internalized stigma mediated the effect of linkage to care on depression. Furthermore, participants who had both linked to HIV care and initiated antiretroviral therapy reported the lowest levels of depressive symptoms. CONCLUSIONS: These results provide further support for current efforts to ensure that women who are newly diagnosed with HIV during pregnancy become linked to HIV care as early as possible, with important benefits for both physical and mental health

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

Fibroblast growth factor receptor 3 (FGFR3) is one of four high-affinity tyrosine kinase receptors for the FGF family of ligands, frequently associated with growth arrest and induction of differentiation. The extracellular immunoglobulin (IgG)-like domains II and III are responsible for ligand binding; alternative usage of exons IIIb and IIIc of the Ig-like domain III determining the ligand-binding specificity of the receptor. By reverse transcriptase polymerase chain reaction (RT–PCR) a novel FGFR3IIIc variant FGFR3IIIS, expressed in a high proportion of tumours and tumour cell lines but rarely in normal tissues, has been identified. Unlike recently described nonsense transcripts of FGFR3, the coding region of FGFR3IIIS remains in-frame producing a novel protein. The protein product is coexpressed with FGFR3IIIc in the membrane and soluble cell fractions; expression in the soluble fraction is decreased after exposure to bFGF but not aFGF. Knockout of FGFR3IIIS using antisense has a growth-inhibitory effect in vitro, suggesting a dominant-negative function for FGFR3IIIS inhibiting FGFR3-induced growth arrest. In summary, alternative splicing of the FGFR3 Ig-domain III represents a mechanism for the generation of receptor diversity. FGFR3IIIS may regulate FGF and FGFR trafficking and function, possibly contributing to the development of a malignant phenotype