Intracellular delivery by membrane disruption: Mechanisms, strategies, and concepts

© 2018 American Chemical Society. Intracellular delivery is a key step in biological research and has enabled decades of biomedical discoveries. It is also becoming increasingly important in industrial and medical applications ranging from biomanufacture to cell-based therapies. Here, we review techniques for membrane disruption-based intracellular delivery from 1911 until the present. These methods achieve rapid, direct, and universal delivery of almost any cargo molecule or material that can be dispersed in solution. We start by covering the motivations for intracellular delivery and the challenges associated with the different cargo typesñYsmall molecules, proteins/peptides, nucleic acids, synthetic nanomaterials, and large cargo. The review then presents a broad comparison of delivery strategies followed by an analysis of membrane disruption mechanisms and the biology of the cell response. We cover mechanical, electrical, thermal, optical, and chemical strategies of membrane disruption with a particular emphasis on their applications and challenges to implementation. Throughout, we highlight specific mechanisms of membrane disruption and suggest areas in need of further experimentation. We hope the concepts discussed in our review inspire scientists and engineers with further ideas to improve intracellular delivery

Pain-related beliefs among Chinese patients with chronic pain: The construct and concurrent predictive validity of the Chinese version of the survey of pain attitudes-14 (ChSOPA-14)

Context: Pain beliefs as indexed by the Survey of Pain Attitudes (SOPA) have been consistently shown to predict pain adjustment outcomes in Western populations. However, its utility in non-Western populations is unclear. Objectives: We evaluated the construct and predictive validity of the Chinese version of the 14-item SOPA (ChSOPA-14) in a sample of Chinese patients with chronic pain. Methods: A total of 208 Chinese patients with chronic musculoskeletal pain completed the ChSOPA-14, the Chronic Pain Grade questionnaire, the Pain Catastrophizing Scale, the Center for Epidemiological Studies-Depression Scale, and measures of sociodemographic characteristics. Results: Except Medical Cure, all ChSOPA-14 scales were significantly correlated with validity criterion measures (all P < 0.05) in expected directions. The present Chinese sample scored the highest on the Medical Cure scale (mean = 2.98, standard deviation [SD] = 1.05) but the lowest on the Disability scale (mean = 1.75, SD = 1.67). Results of hierarchical multiple regression analyses showed that the ChSOPA-14 scales predicted concurrent depression (F(7,177) = 14.51, P < 0.001) and pain disability (F(7,180) = 8.77, P < 0.001). Pain Control (stdβ [standardized beta coefficient] = -0.13; 95% confidence interval [CI]: -3.41, -0.13; P < 0.05) and Emotion (stdβ = 29; 95% CI: 1.76, 5.02; P < 0.001) emerged as significant independent predictors of concurrent depression whereas Disability (stdβ = 0.19; 95% CI: 1.33, 7.88; P < 0.01), Emotion (stdβ = 16; 95% CI: 0.08, 7.59; P < 0.05), and Solicitude (stdβ = -0.14; 95% CI: -7.05, -0.04; P < 0.05) significantly associated with concurrent disability. Conclusion: The findings offer preliminary evidence for the construct and concurrent predictive validity of the ChSOPA-14. This makes available a suitable instrument for chronic pain in the Chinese population and will facilitate future cross-cultural research on pain beliefs. © 2011 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.postprin

Pain education for patients with non-specific low back pain in Nepal: Protocol of a feasibility randomised clinical trial (PEN-LBP Trial)

Introduction Low back pain (LBP) is the leading cause of years lived with disability in Nepal and elsewhere. Management of LBP that is evidence-based, easily accessible, cost-effective and culturally appropriate is desirable. The primary aim of this feasibility study is to determine if it is feasible to conduct a full randomised clinical trial evaluating the effectiveness of pain education as an intervention for individuals with LBP in Nepal, relative to guideline-based physiotherapy treatment. The findings of the study will inform the planning of a full clinical trial and if any modifications are required to the protocol before undertaking a full trial. Methods/analysis This protocol describes an assessor-blinded feasibility clinical trial investigating feasibility of the pain education intervention in patients with non-specific LBP in a physiotherapy hospital in Kathmandu, Nepal. Forty patients with LBP will be randomly allocated to either pain education or guideline-based physiotherapy treatment (control). Outcomes will be assessed at baseline and at a 1 week post-treatment. The primary outcomes are related to feasibility, including: (1) participant willingness to participate in a randomised clinical trial, (2) feasibility of assessor blinding, (3) eligibility and recruitment rates, (4) acceptability of screening procedures and random allocation, (5) possible contamination between the groups, (6) intervention credibility, (7) intervention adherence, (8) treatment satisfaction and (9) difficulty in understanding the interventions being provided. Ethics/dissemination The protocol was approved by Nepal Health Research Council (NHRC; registration number: 422/2017) and University of Otago Human Ethics Committee for Health (registration number: H17/157). The results of the study will be presented at national and international conferences and published in a peer-reviewed journal. Trial registration number NCT03387228; Pre-results

Results of a feasibility randomised clinical trial on pain education for low back pain in Nepal: The Pain Education in Nepal-Low Back Pain (PEN-LBP) feasibility trial

Objectives The aims of this study were to: (1) develop pain education materials in Nepali and (2) determine the feasibility of conducting a randomised clinical trial (RCT) of a pain education intervention using these materials in Nepal. Design A two-arm, parallel, assessor-blinded, feasibility RCT. Setting A rehabilitation hospital in Kathmandu, Nepal. Participants Forty Nepalese with non-specific low back pain (mean [SD] age 41 [14] years; 12 [30%] women). Interventions Eligible participants were randomised, by concealed, 1:1 allocation, to one of two groups: (1) a pain education intervention and (2) a guideline-based physiotherapy active control group intervention. Each intervention was delivered by a physiotherapist in a single, 1-hour, individualised treatment session. Primary outcome measures The primary outcomes were related to feasibility: recruitment, retention and treatment adherence of participants, feasibility and blinding of outcome assessments, fidelity of treatment delivery, credibility of, and satisfaction with, treatment. Assessments were performed at baseline and at 1 week post-treatment. Secondary outcome measures Pain intensity, pain interference, pain catastrophising, sleep disturbance, resilience, global rating of change, depression and quality of life. Statistical analyses were conducted blind to group allocation. Results Forty participants were recruited. Thirty-eight participants (95%) completed the 1-week post-treatment assessment. Most primary outcomes surpassed the a priori thresholds for feasibility. Several findings have important implications for designing a full trial. Secondary analyses suggest clinical benefit of pain education over the control intervention, with larger decrease in pain intensity (mean difference=3.56 [95% CI 0.21 to 6.91]) and pain catastrophising (mean difference=6.16 [95% CI 0.59 to 11.72]) in the pain education group. Pain intensity would seem an appropriate outcome for a full clinical trial. One minor adverse event was reported. Conclusion We conclude that a full RCT of pain education for back pain in Nepal is feasible and warranted. Trial registration number NCT03387228; Results

Socioeconomic factors, psychological factors, and function in adults with chronic musculoskeletal pain from rural Nepal

Background: Both socioeconomic and psychological factors have been shown to predict patient function in samples of individuals with chronic pain in Western countries. However, little is known about their role as predictors of function in individuals with chronic pain from developing countries. Purpose: The purpose of this study was to examine the associations between measures of socioeconomic factors (income, education) and psychological factors (catastrophizing and resilience) and measures of function in a sample of individuals with chronic pain from rural Nepal. In addition, we sought to evaluate the moderating effects of socioeconomic factors on the associations between the psychological variables and function. Methods: We interviewed 143 adults with chronic musculoskeletal pain from rural areas of Nepal to assess income, education level, pain intensity, catastrophizing, resilience, physical function, and depression. We performed two regression analyses to evaluate the direct and unique effects of the socioeconomic and psychological variables and pain intensity as predictors of patient function, as well as the moderating influence of income, education level, and pain intensity on the associations between the psychological variables and function. Results: Education and income both predicted physical function, but only income predicted depression. In addition, pain catastrophizing, but not resilience, evidenced a direct and significant independent association with depression. Neither catastrophizing nor resilience made independent and significant direct contributions to the prediction of physical function. The association between resilience and physical function was moderated by pain intensity and income, and income (but not education or pain intensity) moderated the associations between both 1) resilience and depression and 2) catastrophizing and depression. Conclusion: The results suggest the possibility that cultural differences may influence the role that psychosocial factors play in chronic pain adjustment. These findings have important implications regarding how psychosocial pain interventions should be adapted by individuals in developing countries

Beyond Dexamethasone, Emerging Immuno-Thrombotic Therapies for COVID-19

Host immunity is required to clear SARS‐CoV‐2, and inability to clear the virus because of host or pathogen factors renders those infected at risk of poor outcomes. Estimates of those who are able to clear the virus with asymptomatic or paucisymptomatic COVID‐19 remain unclear, and dependent on widespread testing. However, evidence is emerging that in severe cases, pathological mechanisms of hyperinflammation and coagulopathy ensue, the former supported by results from the RECOVERY trial demonstrating a reduction in mortality with dexamethasone in advanced COVID‐19. It remains unclear whether these pathogenic pathways are secondary to a failure to clear the virus because of maladaptive immune responses or if these are sequential COVID‐19 defining illnesses. Understanding the pathophysiological mechanisms underpinning these cascades is essential to formulating rationale therapeutic approaches beyond the use of dexamethasone. Here, we review the pathophysiology thought to underlie COVID‐19 with clinical correlates and the current therapeutic approaches being investigated

The chronic pain coping inventory: Confirmatory factor analysis of the French version

BACKGROUND: Coping strategies are among the psychosocial factors hypothesized to contribute to the development of chronic musculoskeletal disability. The Chronic Pain Coping Inventory (CPCI) was developed to assess eight behavioral coping strategies targeted in multidisciplinary pain treatment (Guarding, Resting, Asking for Assistance, Task Persistence, Relaxation, Exercise/Stretch, Coping Self-Statements and Seeking Social Support). The present study had two objectives. First, it aimed at measuring the internal consistency and the construct validity of the French version of the CPCI. Second, it aimed to verify if, as suggested by the CPCI authors, the scales of this instrument can be grouped according to the following coping families: Illness-focused coping and Wellness-focused coping. METHOD: The CPCI was translated into French with the forward and backward translation procedure. To evaluate internal consistency, Cronbach's alphas were computed. Construct validity of the inventory was estimated through confirmatory factor analysis (CFA) in two samples: a group of 439 Quebecois workers on sick leave in the sub-acute stage of low back pain (less than 84 days after the work accident) and a group of 388 French chronic pain patients seen in a pain clinic. A CFA was also performed to evaluate if the CPCI scales were grouped into two coping families (i.e. Wellness-focused and Illness-focused coping). RESULTS: The French version of the CPCI had adequate internal consistency in both samples. The CFA confirmed the eight-scale structure of the CPCI. A series of second-order CFA confirmed the composition of the Illness-focused family of coping (Guarding, Resting and Asking for Assistance). However, the composition of the Wellness-focused family of coping (Relaxation, Exercise/Stretch, Coping Self-Statements and Seeking Social Support) was different than the one proposed by the authors of the CPCI. Also, a positive correlation was observed between Illness and Wellness coping families. CONCLUSION: The present study indicates that the internal consistency and construct validity of the French version of the CPCI were adequate, but the grouping and labeling of the CPCI families of coping are debatable and deserve further analysis in the context of musculoskeletal and pain rehabilitation

Preliminary Psychometric Properties of the Chinese Version of the Chronic Pain Coping Inventory (ChCPCI) in a Hong Kong Chinese Population

The Chronic Pain Coping Inventory (CPCI) is a frequently used measure that assesses 8 categories of coping strategies that patients might use to cope with chronic pain. Despite its good psychometric properties and widespread use, the instrument has not been tested for its applicability and validity in non-Western populations, such as among Chinese. This study evaluated the reliability and validity of a Chinese translation of the 42-item CPCI (ChCPCI-42) in a sample of Chinese patients with chronic pain (n = 208). In addition to the ChCPCI-42, the patients were administered the Chronic Pain Grade (CPG) questionnaire, the Pain Catastrophizing Scale (PCS), the Centre for Epidemiological Studies-Depression Scale (CES-D), and questions assessing sociodemographic characteristics. Results of confirmatory factor analyses revealed that of the ChCPCI-42 8 scales, 6 demonstrated acceptable-to-good data-model fit (CFI ≥ 0.90) and 2 demonstrated medium fit (CFI ≥ 0.85). The 8 scales demonstrated adequate to good internal consistency (Cronbach α, 0.69 to 0.79) and correlated with CES-D, PCS, pain intensity, and disability in expected directions. Results of hierarchical multiple regression analyses showed that the ChCPCI-42 scales predicted concurrent depression (F (8,177) = 3.07, P < .01) and pain disability (F (1, 179) = 4.35, P < .001) scores, the Task Persistence scale being the strongest unique predictor among the 8 scales. The findings support the factorial validity and reliability of a 42-item CPCI that can be used among Chinese patients with chronic pain. Perspective: The report outlines the first validation of the CPCI for use in Hong Kong Chinese. This makes available a suitable instrument for chronic pain research in the Southern Chinese population and will help to elucidate similarities and differences in pain coping between Chinese and other ethnic groups. © 2010 American Pain Society.postprin

Group Differences Between Countries and Between Languages in Pain-Related Beliefs, Coping, and Catastrophizing in Chronic Pain: A Systematic Review

Objective: To evaluate the extent to which pain-related beliefs, appraisals, coping, and catastrophizing differ between countries, language groups, and country economy. / Design: Systematic review. / Methods: Two independent reviewers searched 15 databases without restriction for date or language of publication. Studies comparing pain beliefs/appraisals, coping, or catastrophizing across two or more countries or language groups in adults with chronic pain (pain for longer than three months) were included. Two independent reviewers extracted data and performed the quality appraisal. Study quality was rated as low, moderate, or high using a 10-item modified STROBE checklist. Effect sizes were reported as small (0.20–0.49), medium (0.50–0.79), or large (≥0.80). / Results: We retrieved 1,365 articles, read 42 potential full texts, and included 10 (four moderate-quality, six low-quality) studies. A total of 6,797 adults with chronic pain (33% with chronic low back pain) were included from 16 countries. Meta-analysis was not performed because of heterogeneity in the studies. A total of 103 effect sizes were computed for individual studies, some of which indicated between-country differences in pain beliefs, coping, and catastrophizing. Of these, the majority of effect sizes for pain beliefs/appraisal (60%; eight large, eight medium, and eight small), for coping (60%; seven large, 11 medium, and 16 small), and for catastrophizing (50%; two medium, one small) evidenced statistically significant between-country differences, although study quality was low to moderate. / Conclusions: In 50% or more of the studies, mean scores in the measures of pain beliefs and appraisals, coping responses, and catastrophizing were significantly different between people from different countries