Inadequate Relief Research Articles

Repeat gamma knife stereotactic radiosurgery in the treatment of trigeminal neuralgia: A single-center experience and focused review of the literature

ObjectivesRepeat Gamma Knife stereotactic radiosurgery (GKSR) for refractory trigeminal neuralgia (TGN) is an increasingly common practice. Prior studies have reported varying success rates and incidence of trigeminal nerve dysfunction following repeated GKSR. We report treatment outcomes and toxicity in patients following repeat GKSR for TGN at the University of Alabama at Birmingham (UAB) with a focused review of the literature. MethodsWe retrospectively reviewed medical records of 55 TGN patients re-treated with radiosurgery using the Leksell Gamma Knife® at the University of Alabama at Birmingham between 1996 and 2012. Outcomes were defined using the Modified Marseille Scale. Demographics, prior treatments and symptom duration were correlated with outcomes. ResultsEighteen patients (33%) achieved Marseille Class I or II, 14 (25%) Class III or IV, and 23 (42%) Class V at a mean follow-up of 14.4 months. Twenty-five patients (45%) developed new trigeminal nerve dysfunction after re-treatment. Of these, four (16%) did not develop dysfunction until subsequent microvascular decompression (MVD) for inadequate symptom relief. ConclusionsAlthough more than half of the patients undergoing repeat GKSR for refractory TGN maintained excellent or good outcomes (Marseille classes I–IV) at an average follow-up of 14.4 months, neither age, gender, nor pre-treatment duration of symptoms or interval between treatments had a statistically significant effect on outcomes. Following repeat GKSR, patients have increased risk for new-onset trigeminal nerve dysfunction and those undergoing MVD after repeat GKSR may have an increased risk for new-onset trigeminal nerve dysfunction.

The Immediate Results of Percutaneous Balloon Aortic Valvuloplasty in Patients with Congenital Aortic Valvular Stenosis

Objective: To assess the immediate-term effectiveness of percutaneous balloon aortic valvuloplasty (PBAV) for congenital aortic stenosis (AS). Design: Early clinical and instrumental evaluation of 34 consecutive PBAV performed from 2001 to 2007. Setting:  A tertiary referral center for heart diseases (Ibn Al-Bitar Cardiac Center). Patients: Thirty-four patients with congenital valvular AS, twenty-five males and nine females. Interventions: PBAV using Tayshak balloons of different sizes and lengths. Main outcome measures:  Doppler and peak to peak pressure gradient (PG) across the aortic valve (AV) before and after valvuloplasty, the percent of PG reduction post dilatation, left ventricular (LV) systolic and diastolic pressures before and after valvuloplasty, number of the aortic cusps, degree of aortic regurgitation (AR) before and after valvuloplasty, left ventricular systolic function before and after valvuloplasty, associated anomalies,  and the need for emergency surgery were the main outcome measures. Results: The peak to peak instantaneous PG across the AV was reduced acutely from 102 ± 42.7 (20 - 200) mm Hg to 40 ± 25.5 (10- 140) mm Hg (p<0.001), left ventricular systolic pressure was reduced from 196 ± 48.57 (70 – 280) mm Hg to 133 ± 35.45 (65 – 240) mm Hg (p<0.001) and both are statistically significant. Three patients had inadequate relief of obstruction but in one of them it was mainly due to subaortic obstruction and two patients had severe AR, one of them with acute pulmonary edema and required surgical AV repair. PBAV produced a gradient reduction ≥ 50% in 29 patients, six patients having a residual peak to peak gradient of >50 mm Hg and in one of whom the remaining PG was 70 mm Hg which was mainly subvalvular (50 mm Hg). Six patients had bicuspid AV while the other patients had tricuspid valve. Six had associated anomalies. There was no mortality during the procedure. Severe AR reported in two patients and moderate AR occurred in five patients. One significant complication (acute pulmonary edema) occurred immediately after the dilatation and surgery was done for that patient after few days. Two serious complications occurred during the procedure which responded to routine resuscitation. There was a residual maximum Doppler gradient of < 30 mm Hg in 12 patients, ≥ 60 mm Hg in four (one of them had mainly subvalvular gradient) and between 30 to 48 mm Hg in the others. Twenty one patients developed new AR (62%), in fourteen of them (41%) it was mild. Conclusions: PBAV is an effective procedure and offers a good palliation for congenital AS.

Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as A Therapeutic Strategy for Alphaviral Disease

Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined.

(271) Attitudes of Older Adults with Chronic Musculoskeletal Pain towards Immersive Virtual Reality

Older adults are especially susceptible to chronic musculoskeletal (MSK) pain. Drugs provide inadequate relief and overuse can lead to adverse events. Immersive virtual reality (IVR), a computer-generated simulation of a 3-D image, can act as distraction therapy by drawing attention away from pain. The purpose of this study is to explore the attitudes and treatment acceptability of older adults with chronic MSK pain towards IVR as distraction therapy for chronic pain exacerbations. The aims are: 1) describe attitudes of older adults suffering from chronic MSK pain towards IVR using focus groups; 2) describe IVR treatment acceptability and side effects using surveys. This is a descriptive, exploratory study using mixed methods and convergent parallel design. Inclusion criteria: 1) diagnosis of chronic MSK pain; 2) 65 and older; 3) residency at participating facility. Exclusion criteria: 1) cognitive impairment; 2) hearing/visual deficit. Treatment acceptability was measured with 8 items scored on a 5-pt Likert scale. Side effects to IVR were measured with Virtual Reality Sickness Questionnaire (VRSQ). Participation consisted of 2 visits. The first visit included the consent process, eligibility screening, survey completion, and 15-minutes of IVR and the second visit was a focus group. Data collection and analysis is ongoing, and the current sample size is 15. Most participants found IVR to be an acceptable way to manage pain (73.4%) and would be willing to use it for their pain (73.3%). 46.6% believed it would likely reduce their pain. Few experienced side effects (26%), such as general discomfort and eyestrain. Qualitative data suggests: 1) greater ease of use with sufficient practice; 2) a preference towards relaxation, meditation, or biofeedback simulations with realistic images; 3) an uncertainty of effectiveness with movement-evoked pain. The findings of this study will help optimize IVR as a therapy for chronic MSK pain.

Clinical Assessment and Management of Foot and Ankle Osteoarthritis: A Review of Current Evidence and Focus on Pharmacological Treatment.

Foot and ankle osteoarthritis (OA) is a common and disabling problem that adversely affects physical function and significantly reduces quality of life. Although the knee was considered to be the lower-limb site most often affected by OA, recent population data showed foot OA is as prevalent as knee OA, and rates increase with advancing years. The most common foot OA sites include the first metatarsophalangeal joint and the midfoot, with the ankle affected less often. Despite the high prevalence and disabling nature of foot and ankle OA, the condition has been neglected by clinical researchers, and there are very few trials investigating non-surgical foot or ankle OA treatment options. There are no accepted clinical diagnostic criteria for foot or ankle OA so imaging remains common. Clinical guidelines based on knee and hip OA research recommend education, exercise, and weight loss in the first instance. Topical non-steroidal anti-inflammatory drugs (NSAIDs) or capsaicin may be used as an adjunct. Failing these approaches, acetaminophen (paracetamol) should be recommended; however, if there is inadequate symptomatic relief, then clinicians should trial an oral NSAID or a cyclo-oxygenase-2 inhibitor. Given that adverse events and co-morbidities are common in the elderly, older patients should be closely monitored. Some studies have investigated intra-articular injections for foot and ankle OA, and there is some evidence to suggest hyaluronic acid may be effective in the short term for ankle OA. With the lack of research on foot or ankle OA treatments, however, robust clinical trials are urgently needed.

Research on Experience Model of Precision Poverty Alleviation in S Village—Based on the Perspective of Policy Implementation Process Theory

Overcoming poverty is the top priority of the 13th Five-Year Plan and the key to achieving the first century-long goal of a well-off society in an all-round way. With the continuous advancement of poverty alleviation work in China, the poverty alleviation work has encountered various difficulties, such as “the scattered distribution of poor households, multiple causes of poverty, and inadequate poverty relief”, and the effectiveness of poverty alleviation has been weakened. Against this background, General Secretary Xi Jinping made important instructions on “targeted poverty alleviation” and successively introduced related policies on targeted poverty alleviation in the following years, opening a new chapter for China’s poverty alleviation. Based on the social background of the “China Highlights, World Model” poverty alleviation effect in Guangdong Province, this paper selects the “S Village in Qingyuan City” to carry out field research, elaborates the existing poverty alleviation projects in S Village, and uses Smith policy to perform theoretical analysis, and analyzes the reasons for its effectiveness. Through analysis, it is found that the reason for the outstanding effect of poverty alleviation in S Village is that the poverty alleviation subjects such as the village poverty alleviation task force made full use of poverty reduction policies support, faced the poor households who were desperate to get rid of poverty, accurately analyzed their causes of poverty, and adopted corresponding poverty alleviation measures to stimulate. The endogenous drive for poverty alleviation of poor households was achieved, and the goal of joint efforts for poverty alleviation was achieved. Finally, this article builds an effective and targeted poverty alleviation system based on the effectiveness of poverty alleviation in S Village. Targeting both sides of poverty alleviation is the foundation, achieving the precise supply and demand of poor households is the key, implementing the responsibility of both sides is fundamental, and using appropriate means of poverty alleviation is the guarantee.

Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias.

Hereditary spastic paraplegias (HSPs) are a large group of genetically-diverse neurologic disorders characterized clinically by a common feature of lower extremity spasticity and gait difficulties. Current therapies are predominantly symptomatic, and even then usually provide inadequate relief of symptoms. Going forward, HSP therapeutics development requires a systematic analysis of quantifiable measures and tools to assess treatment response. This review summarizes promising therapeutic targets, assessment measures, and previous clinical trials for the HSPs. Oxidative stress, signaling pathways, microtubule dynamics, and gene rescue/replacement have been proposed as potential treatment targets or modalities. Quantitative evaluation of pre-clinical rodent HSP models emphasize rotarod performance, foot base angle, grip strength, stride length, beam walking, critical speed, and body weight. Clinical measures of HSP in humans include 10-m gait velocity, the Spastic Paraplegia Rating Scale (SPRS), Ashworth Spasticity Scale, Fugl-Meyer Scale, timed up-and-go, and the Gillette Functional Assessment Questionnaire. We conducted a broad search for past clinical trials in HSPs and identified trials that investigated pharmacological agents including atorvastatin, gabapentin, L-threonine, botulinum toxin, dalfampridine, methylphenidate, and baclofen. We provide recommendations for future HSP treatment directions based on these prior research experiences as well as regulatory insight.

Nerve blocks in paediatric and adolescent headache disorders.

Headaches in children and adolescents are common, causing debilitating symptoms in many. Treatment of headache disorders can be complex and standard lifestyle changes as well as oral medications may offer inadequate relief. The purpose of this article is to review the mechanism of action, efficacy and technique of peripheral nerve blocks (PNBs) and the role they play in treating paediatric headache disorders. Evidence for the use of PNBs in youth is limited. However, available studies show evidence of benefit in both primary and secondary headache disorders. Variability exists in the type of block, medication choice, volume infused and frequency of this treatment. There are no serious side effects associated with PNBs. PNBs are well tolerated and effective as adjunctive therapy for many disabling paediatric headache disorders. The technique can be easily learned by frontline and specialty practitioners. Prospective placebo-controlled studies are needed to determine how to best maximize PNBs for headache management (i.e. medication choice, timing and so on).

Postoperative Pain Management: A Bedside Perspective

Purpose: Postoperative pain management is an ongoing challenge in surgical care, during which inadequate relief can contribute to postoperative complications, and nurses are key figures in this process. The aim of the present study was to gain knowledge of how nurses provide postoperative pain management for women undergoing major surgery for endometriosis. Design: An ethnographic field study, consisting of semi-structured interviews and participant observations, was conducted in a setting of 2 gynecological units within a large Scandinavian university hospital. Method: The participants were mainly nurses and patients. The overall focus for the field observations and interviews was on how the participants interacted and made care decisions concerning pain. The analysis focused on nurse-patient interaction in postoperative bedside care. A principal theme, pain-related nursing practice emerged, together with the sub-themes nurse-patient interaction, interpretation and assessment of pain and pain management, which represented a circular process, identified in bedside practice. Conclusions: To some extend the postoperative pain management was influenced by unexpressed health beliefs and routine actions, and patient involvement was not prominent. Furthermore, the existing guidelines for pain management did not seem useful to the nurses. Clinical implications: There is a need to develop a new and more practice-oriented postoperative pain management, in ways that also integrate the patient experience.

Photoaffinity‐Mediated Identification of a Third Citalopram Analog Binding Site on the Serotonin Transporter

In the CNS, serotonin (5HT) controls anxiety and mood, and disorders caused by imbalanced 5HT include Major Depressive Disorder and Autism Spectrum Disorder. The serotonin transporter (SERT) is a major regulator of synaptic 5HT levels and is the target for antidepressants such as escitalopram (S‐CIT) and fluoxetine, which bind to and inhibit the transporter to elevate free transmitter. The efficacy of these drugs is moderate and many patients experience inadequate relief, indicating the need for better understanding of mechanisms or development of novel therapeutics. Antidepressant effects on SERT are complex, as many induce high‐affinity actions at the S1 orthosteric site, as well as allosteric modulation of S1 function through low‐affinity binding to a distinct S2 domain. To examine S‐CIT mechanisms we developed two novel photoaffinity ligands, [125I]VK 03‐83 and [125I]VK 03‐51, that possess identical S‐CIT pharmacophores but have cross‐linking moieties appended to different positions on the citalopram core. Our findings show that both ligands bind to SERT, inhibit 5HT transport, and allosterically regulate S1 function, but display distinct pharmacological characteristics that indicate differential binding mechanisms. [125I]VK 03‐83 labeling of SERT is fully inhibited by 5HT and typical SERT inhibitors, with an S‐CIT Ki of ~1 nM, consistent with binding to S1. In contrast, although [125I]VK 03‐51 labeling is fully displaced by the homologous ligand, it is inhibited only ~30% by S‐CIT or other standard SERT inhibitors, and shows no displacement by 10 μM 5HT, indicative of binding to multiple sites. The S‐CIT‐displaceable portion of [125I]VK 03‐51 labeling occurs with a Ki of ~1 nM, consistent with binding at S1, whereas the fraction of labeling that is not sensitive to ≥10 μM concentrations of S‐CIT, other inhibitors, or 5HT likely does not occur at either S1 or S2, which should both be fully occupied by these conditions. These findings suggest that [125I]VK 03‐51 interacts with SERT at a third site that has not been previously detected by reversible binding or co‐crystallization approaches, but is revealed by covalent cross‐linking. This site may function in transport inhibition or allosteric regulation, and suggests a domain for exploration of transporter mechanisms or medication development.Support or Funding InformationNIH DA027845 and UNDSMHS Seed Grant (LKH and RAV), NIDA Intramural Research Program (AHN)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute Pediatric Pain Management in the Primary Care Office.

Pain is a chief complaint in children seeking medical care, yet it may also be experienced in evaluation and treatment during office visits. Inadequate relief of children's procedural pain and distress not only affects the experience of the children and their parents, but also adversely affects procedural outcomes. Despite increasing awareness and research, management of procedural pain and anxiety in children is often inadequate. In addition, parent and patient satisfaction is often tied to pain management. Development of a pain management plan must be systematic, individualized, and multimodal. We present a review of nonpharmacologic modalities, topical and oral analgesic agents, and intranasal adjuncts for use in routine outpatient practice. [Pediatr Ann. 2018;47(3):e124-e129.].

Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer\u2019s disease by exerting anti-inflammatory and neuroprotective effects

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

Efficacy of cardiac shock wave therapy in patients with stable angina: The design of randomized, triple blind, sham-procedure controlled study

Objective:Despite revascularization and optimal medical treatment (OMT), patients with angina often have a reduced quality of life due to inadequate relief from symptoms. Recent studies have shown that the application of shock waves may reduce angina symptoms and improve quality of life, exercise capacity, and myocardial perfusion due to the stimulation of angiogenesis. However, there is limited evidence due to small, single-arm, single-center studies of low to moderate quality. The purpose of this study is to evaluate the impact of cardiac shock wave therapy (CSWT) on exercise tolerance and angina symptoms in patients with coronary artery disease and objective evidence of myocardial ischemia who cannot undergo traditional revascularization and experience angina despite OMT in comparison to sham procedure.Methods:We designed a randomized, triple-blind, placebo-controlled, multicentre trial (NCT02339454) to assess the efficacy of CSWT in addition to OMT in patients with stable angina and myocardial ischemia documented by exercise treadmill test (ETT). All patients were treated with stable doses of standard medical treatment 4 weeks before screening. An increase in the total exercise duration on ETT by ≥90 s from the baseline at the end of the study was set as the primary endpoint. Secondary endpoints included angina class, Seattle angina questionnaire scores, symptoms, and ECG changes during stress test. Patients underwent nine sessions of CSWT or corresponding sham procedure applied to all segments of the left ventricle, within 9 weeks. Endpoint assessments were performed at 6-month follow-up. The imaging substudies assessed the potential of CSWT to reduce stress-induced myocardial ischemia detected by dobutamine stress echocardiography, cardiac single-photon emission computed tomography, and cardiac magnetic resonance imaging.Results:At two centers, 72 of the 323 screened patients were randomized in two groups (ratio 1:1): active treatment and placebo control. Study patients were predominantly males (70.8%); the mean age of the patients was 68.4±8.3 years. Of these, 44 patients had angina Canadian Cardiovascular Society class III, and 66.7% of the patients had a history of myocardial infarction.Conclusion:Using sham applicators, blinding study participants, investigators, and endpoints assessors to the study data as well as centralized randomization ensures rigorous methodology and low risk of bias in this large randomized controlled CSWT study.

Does septal thickness influence outcome of myectomy for hypertrophic obstructive cardiomyopathy?

Patients with hypertrophic obstructive cardiomyopathy and basal septal thickness <18 mm are often considered unsuitable candidates for myectomy. Mitral valve (MV) replacement is frequently performed instead. We aimed to determine whether septal thickness affects outcomes and adequacy of myectomy. Clinical and echocardiographic data were reviewed for 1486 consecutive adult patients with hypertrophic obstructive cardiomyopathy who underwent transaortic septal myectomy from January 2005 through December 2014. Comparisons between patients, grouped by septal thickness (<18 mm, n = 369; 18-21 mm, n = 612 and >21 mm, n = 505), were performed with the Kruskal-Wallis and the Pearson χ2 tests and semiparametric analysis of covariance. Median group ages were 57, 57 and 54 years (P = 0.007); men comprised 50.4%, 56.7% and 62.0%, respectively (P = 0.003). Intrinsic MV disease was present in 5.9%, 5.2% and 4.6%, respectively (P = 0.80). All patients underwent transaortic septal myectomy. Additional mitral procedures were performed in 7.6%, 7.8% and 8.1%, respectively (P = 0.90). Reasons for MV surgery included intrinsic MV disease (66.7%), residual mitral regurgitation (30.8%) and residual gradient (2.6%). All groups had postoperative gradient relief (median reduction: 51, 54 and 50 mmHg; P = 0.11). Ventricular septal defect occurred in 4 patients (0.3%), and risk did not differ by group (P = 0.24). Adequate relief of left ventricular outflow tract obstruction can be achieved via transaortic septal myectomy without concomitant MV procedures when septal thickness is < 18 mm, and the risk of ventricular septal defect is minimal. Concomitant MV repair/replacement should be reserved for patients with intrinsic MV disease or inadequate relief of mitral regurgitation/left ventricular outflow tract obstruction following adequate extended septal myectomy.

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial.

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases. To assess the analgesic efficacy of adjunctive Sativex (Δ9-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy. This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design). The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00-17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: -5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified. Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted.

Failure analysis of the wall tubes of a water-tube boiler

Abstract An industrial case history of the failure of the evaporator (water wall) tubes of a water-tube boiler is presented in this study. After two years in service, a leak was detected in one of the tubes over its bent section with pitting corrosion on its internal surface. Later on, the same symptoms were discovered in other tubes of the same boiler, and several tubes were extracted for failure analysis. On the basis of visual inspection, chemical analysis, microstructural examination, hardness measurements, and residual stress measurements via X-ray diffraction (XRD), the failure mechanism of the tubes was identified as stress corrosion cracking (SCC). In this paper, the results obtained from the experimental analysis are summarized, and finite element (FE) models are used to predict the residual stress due to the bending of the tube and the operational stress at the moment of failure. It was found that tensile residual stress from an inadequate stress relief treatment prior to service and high concentration of dissolved oxygen in the feed water were the main reasons for the premature failure of the boiler tubes by SCC.

The Epilepsy Dilemma.

The article focuses on the failure of current medicines to relieve seizures in about a third of people with epilepsy in the U.S. Topics covered include the inadequate relief from medication received by patients despite the introduction of more than a dozen new antiepileptic drugs since 1990, new approaches to treating epilepsy, such as nutritional approach like the ketogenic diet and surgical techniques, and the potential of cannabidiol as an effective treatment for some forms of epilepsy.

ASHP Guidelines on Preventing Diversion of Controlled Substances.

Controlled substances (CS) diversion in health systems can lead to serious patient safety issues, harm to the diverter, and significant liability risk to the organization. Diversion driven by addiction puts patients at risk of harm, including inadequate relief of pain, inaccurate documentation of

Iranian postmenopausal women’s experiences of treatment of symptomatic vulvovaginal atrophy

Objectives: Our aim was to explore the experiences of Iranian postmenopausal women who sought medical help for their symptomatic vulvovaginal atrophy (VVA).Methods: Five focus group discussions (FGDs) were conducted. Participants had to be postmenopausal; had bothersome symptoms of VVA for which they came to the clinic; had previously sought medical help for their VVA; and had confirmed physical signs of VVA upon examination by a gynecologist.Results: Twenty-five women, aged 49–60 years participated in the five FGDs. Twenty women said they currently had >1 VVA symptom at presentation to the clinic. Four major themes emerged from the women’s narrative stories: (1) negative impact of VVA on women’s life, (2) psychological distress associated with VVA, (3) negative impact of VVA on marriage and relationship, (4) inadequate symptom relief from available treatments due to lack of awareness of VVA treatment options. None of the participants reported ongoing treatment of their VVA with local low-dose estrogen. Women further commented that, although local estrogen products were costly, they would like to use them if they were prescribed.Conclusions: Considering the negative impact of VVA symptoms on women’s lives, health professionals in Iran should be prescribing approved and effective therapies for symptomatic women.