Treatments for Morton's neuroma.

BACKGROUND: Morton's neuroma (MN) is a painful neuropathy resulting from a benign enlargement of the common plantar digital nerve that occurs commonly in the third webspace and, less often, in the second webspace of the foot. Symptoms include burning or shooting pain in the webspace that extends to the toes, or the sensation of walking on a pebble. These impact on weight-bearing activities and quality of life. OBJECTIVES: To assess the benefits and harms of interventions for MN. SEARCH METHODS: On 11 July 2022, we searched CENTRAL, CINAHL Plus EBSCOhost, ClinicalTrials.gov, Cochrane Neuromuscular Specialised Register, Embase Ovid, MEDLINE Ovid, and WHO ICTRP. We checked the bibliographies of identified randomised trials and systematic reviews and contacted trial authors as needed. SELECTION CRITERIA: We included all randomised, parallel-group trials (RCTs) of any intervention compared with placebo, control, or another intervention for MN. We included trials where allocation occurred at the level of the individual or the foot (clustered data). We included trials that confirmed MN through symptoms, a clinical test, and an ultrasound scan (USS) or magnetic resonance imaging (MRI). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed bias using Cochrane's risk of bias 2 tool (RoB 2) and assessed the certainty of the evidence using the GRADE framework. MAIN RESULTS: We included six RCTs involving 373 participants with MN. We judged risk of bias as having 'some concerns' across most outcomes. No studies had a low risk of bias across all domains. Post-intervention time points reported were: three months to less than 12 months from baseline (nonsurgical outcomes), and 12 months or longer from baseline (surgical outcomes). The primary outcome was pain, and secondary outcomes were function, satisfaction or health-related quality of life (HRQoL), and adverse events (AE). Nonsurgical treatments Corticosteroid and local anaesthetic injection (CS+LA) versus local anaesthetic injection (LA) Two RCTs compared CS+LA versus LA. At three to six months: • CS+LA may result in little to no difference in pain (mean difference (MD) -6.31 mm, 95% confidence interval (CI) -14.23 to 1.61; P = 0.12, I2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Assessed via a pain visual analogue scale (VAS; 0 to 100 mm); a lower score indicated less pain.) • CS+LA may result in little to no difference in function when compared with LA (standardised mean difference (SMD) -0.30, 95% CI -0.61 to 0.02; P = 0.06, I2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Function was measured using: the American Orthopaedic Foot and Ankle Society Lesser Toe Metatarsophalangeal-lnterphalangeal Scale (AOFAS; 0 to 100 points) - we transformed the scale so that a lower score indicated improved function - and the Manchester Foot Pain and Disability Schedule (MFPDS; 0 to 100 points), where a lower score indicated improved function.) • CS+LA probably results in little to no difference in HRQoL when compared to LA (MD 0.07, 95% CI -0.03 to 0.17; P = 0.19; 1 study, 122 participants; moderate-certainty evidence), and CS+LA may not increase satisfaction (risk ratio (RR) 1.08, 95% CI 0.63 to 1.85; P = 0.78; 1 study, 35 participants; low-certainty evidence). (Assessed using the EuroQol five dimension instrument (EQ-5D; 0-1 point); a higher score indicated improved HRQoL.) • The evidence is very uncertain about the effects of CS+LA on AE when compared with LA (RR 9.84, 95% CI 1.28 to 75.56; P = 0.03, I2 = 0%; 2 studies, 157 participants; very low-certainty evidence). Adverse events for CS+LA included mild skin atrophy (3.9%), hypopigmentation of the skin (3.9%) and plantar fat pad atrophy (2.6%); no adverse events were observed with LA. Ultrasound-guided (UG) CS+LA versus non-ultrasound-guided (NUG) CS+LA Two RCTs compared UG CS+LA versus NUG CS+LA. At six months: • UG CS+LA probably reduces pain when compared with NUG CS+LA (MD -15.01 mm, 95% CI -27.88 to -2.14; P = 0.02, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). (Assessed with a pain VAS.) • UG CS+LA probably increases function when compared with NUG CS+LA (SMD -0.47, 95% CI -0.84 to -0.10; P = 0.01, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). We do not know of any established minimum clinical important difference (MCID) for the scales that assessed function, specifically, the MFPDS and the Manchester-Oxford Foot Questionnaire (MOXFQ; 0 to 100 points; a lower score indicated improved function.) • UG CS+LA may increase satisfaction compared with NUG CS+LA (risk ratio (RR) 1.71, 95% CI 1.19 to 2.44; P = 0.003, I2 = 15%; 2 studies, 114 feet; low-certainty evidence). • HRQoL was not measured. • UG CS+LA may result in little to no difference in AE when compared with NUG CS+LA (RR 0.42, 95% CI 0.12 to 1.39; P = 0.15, I2 = 0%; 2 studies, 116 feet; low-certainty evidence). AE included depigmentation or fat atrophy for UG CS+LA (4.9%) and NUG CS+LA (12.7%). Surgical treatments Plantar incision neurectomy (PN) versus dorsal incision neurectomy (DN) One study compared PN versus DN. At 34 months (mean; range 28 to 42 months), PN may result in little to no difference for satisfaction (RR 1.06, 95% CI 0.87 to 1.28; P = 0.58; 1 study, 73 participants; low-certainty evidence), or for AE (RR 0.95, 95% CI 0.32 to 2.85; P = 0.93; 1 study, 75 participants; low-certainty evidence) compared with DN. AE for PN included hypertrophic scaring (11.4%), foreign body reaction (2.9%); AE for DN included missed nerve (2.5%), artery resected (2.5%), wound infection (2.5%), postoperative dehiscence (2.5%), deep vein thrombosis (2.5%) and reoperation with plantar incision due to intolerable pain (5%). The data reported for pain and function were not suitable for analysis. HRQoL was not measured. AUTHORS' CONCLUSIONS: Although there are many interventions for MN, few have been assessed in RCTs. There is low-certainty evidence that CS+LA may result in little to no difference in pain or function, and moderate-certainty evidence that UG CS+LA probably reduces pain and increases function for people with MN. Future trials should improve methodology to increase certainty of the evidence, and use optimal sample sizes to decrease imprecision.

A systematic scoping review on the evidence behind debriefing practices for the wellbeing/emotional outcomes of healthcare workers.

Introduction: Debriefings give healthcare workers voice through the opportunity to discuss unanticipated or difficult events and recommend changes. The typical goal of routine debriefings has been to improve clinical outcomes by learning through discussion and reflection of events and then transferring that learning into clinical practice. However, little research has investigated the effects of debriefings on the emotional experiences and well-being of healthcare workers. There is some evidence that debriefings are a multi-faceted and cost-effective intervention for minimising negative health outcomes, but their use is inconsistent and they are infrequently adopted with the specific intention of giving healthcare workers a voice. The purpose of this systematic scoping review is therefore to assess the scope of existing evidence on debriefing practices for the well-being and emotional outcomes of healthcare workers. Methods: Following screening, 184 papers were synthesised through keyword mapping and exploratory trend identification. Results: The body of evidence reviewed were clustered geographically, but diverse on many other criteria of interest including the types of evidence produced, debriefing models and practices, and outcomes captured. Discussion: The current review provides a clear map of our existing understanding and highlights the need for more systematic, collaborative and rigorous bodies of evidence to determine the potential of debriefing to support the emotional outcomes of those working within healthcare. Systematic Review Registration: https://osf.io/za6rj.

Effectiveness of Nonsurgical Interventions for Hallux Valgus: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis investigating the effectiveness of nonsurgical interventions for hallux valgus (HV). METHODS: Medline, CINAHL, Embase, and the Cochrane Library were searched to April 2020, including parallel-group and crossover studies investigating nonsurgical interventions for HV. Two reviewers independently screened articles for inclusion, extracted data, determined risk of bias, and made assessments using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. Risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool. Effect sizes (mean differences or risk ratios, and 95% confidence intervals) were calculated and pooled where possible for the primary outcomes, foot pain, and HV angle. RESULTS: Eighteen included studies investigated a wide range of nonsurgical interventions for HV. Most studies had small sample sizes and concerns regarding risk of bias. Five separate meta-analyses for foot orthoses, splints, manual therapy, and taping added to foot exercises showed no significant effects on primary outcomes. However, results from 8 studies showed a significant pain reduction with the use of foot orthoses, night splints, dynamic splints, manual therapy, taping added to foot exercises, a multifaceted physical therapy program, and Botox injections. Four studies reported a clinically significant reduction in HV angle with night splints, foot exercises, multifaceted physical therapy, and Botox injections. CONCLUSION: There is a low level of certainty surrounding the effectiveness of nonsurgical interventions for HV, but a reduction in pain appears more likely than improvement in HV angle.

The effectiveness of non-surgical interventions for common plantar digital compressive neuropathy (Morton's neuroma): a systematic review and meta-analysis.

BACKGROUND: Morton's neuroma (MN) is a compressive neuropathy of the common plantar digital nerve. It is a common compressive neuropathy often causing significant pain which limits footwear choices and weight bearing activities. This paper aims to review non-surgical interventions for MN, to evaluate the evidence base for the clinical management of MN. METHODS: Electronic biomedical databases (CINAHL, EMBASE, MEDLINE and Cochrane) were searched to January 2018 for studies evaluating the effectiveness of non-surgical interventions for Morton's neuroma. Outcome measures of interest were treatment success rate (SR) (binary) and pain as measured using 100-point visual analogue scale (VAS) (continuous). Studies with and without control groups were included and were evaluated for methodological quality using the Downs and Black Quality Index. Results from randomised controlled trials (RCT) were compared between-groups, and case series were compared pre- versus post-treatment. Effect estimates are presented as odds ratios (OR) for binary data or mean differences (MD) for continuous data. Random effects models were used to pool effect estimates across studies where similar treatments were used. Heterogeneity was assessed using the I 2 statistic. RESULTS: A total of 25 studies met the inclusion criteria, seven RCTs and 18 pre/post case series. Eight different interventions were identified, with corticosteroid or sclerosing injections being the most often reported (seven studies each). Results from a meta-analysis of two RCTs found corticosteroid injection decreased pain more than control on VAS (WMD: -5.3, 95%CI: -7.5 to - 3.2). Other RCTs reported efficacy of: manipulation/mobilisation versus control (MD: -15.3, 95%CI: -29.6 to - 1.0); extracorporeal shockwave therapy versus control (MD: -5.9, 95%CI: -21.9 to 10.1). Treatment success was assessed for extracorporeal shockwave therapy versus control (OR: 0.3, 95%CI: 0.0 to 7.1); and corticosteroid injection vs footwear/padding (OR: 6.0, 95%CI: 1.9 to 19.2). Sclerosing and Botox injections, radiofrequency ablation and cryoneurolysis have been investigated by case series studies, however these were of limited methodological quality. CONCLUSIONS: Corticosteroid injections and manipulation/mobilisation are the two interventions with the strongest evidence for pain reduction, however high-quality evidence for a gold standard intervention was not found. Although the evidence base is expanding, further high quality RCTs are needed.

Inhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small chemical entities.

The interaction of immune complexes with the human Fc receptor, FcgammaRIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three-dimensional structure of an FcgammaRIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand-binding sites. These small chemical entities (SCEs) blocked immune complex-induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for FcgammaRIIa, as they inhibited only immune complex-induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in FcgammaRIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen-induced arthritis (CIA). The SCEs were more potent than methotrexate and anti-CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE FcgammaRIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.

Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses.

Dendrimers are a novel class of polyanionic macromolecules with broad-spectrum antiviral activities and minimal toxicities. A new generation of amide dendrimer, SPL7013, was evaluated as a lead microbicide candidate against herpes simplex viruses (HSV). The plaque reduction assays showed that the 50% effective concentrations (EC(50)) determined by pre-treatment of cells were 2.0 microg/ml for HSV-1 and 0.5 microg/ml for HSV-2. Inhibitory effects were also observed on HSV-infected cells with EC(50)s of 6.1 microg/ml for HSV-1 and 3.8 microg/ml for HSV-2. These are the mean values from the test results of six batches of SPL7013. SPL7013 was also shown to be equally potent against HSV drug-resistant strains. SPL7013 completely inhibited viral adsorption to Vero cells at concentrations of higher than 3 microg/ml. Analyzed by a LightCycler assay after treatment of HSV-infected cells for 17 h, SPL7013 showed strong inhibition of HSV DNA synthesis with EC(50)s of approximately 6.2 and 2.0 microg/ml for HSV-1 and HSV-2, respectively. SPL7013 retained its anti-HSV activity even after treatment at acidic pHs 3.0 and 4.0 for 2 h. The presence of 10% human serum proteins did not affect the anti-HSV activity of SPL7013. SPL7013 was not toxic to Vero cells up to the highest concentration tested (10,000 microg/ml). Effects on cell proliferation were tested on two epithelial cell lines in both stationary and dividing phases. The 50% cytotoxic concentrations (CC(50)) in all cases were greater than 10,000 microg/ml. Our data indicate that SPL7013 is a promising candidate for development as a vaginal microbicide and a therapeutic agent.

Mutations in both env and gag genes are required for HIV-1 resistance to the polysulfonic dendrimer SPL2923, as corroborated by chimeric virus technology.

A drug-resistant NL4.3/SPL2923 strain has previously been generated by in vitro selection of HIV-1(NL4.3) in the presence of the polysulfonic dendrimer SPL2923 and mutations were reported in its gp120 gene (Witvrouw et al., 2000). Here, we further analysed the (cross) resistance profile of NL4.3/SPL2923. NL4.3/SPL2923 was found to contain additional mutations in gp41 and showed reduced susceptibility to SPL2923, dextran sulfate (DS) and enfuvirtide. To delineate to what extent the mutations in each env gene were accountable for the phenotypic (cross) resistance of NL4.3/SPL2923, the gp120-, gp41- and gp160-sequences derived from this strain were placed into a wild-type background using env chimeric virus technology (CVT). The cross resistance of NL4.3/SPL2923 towards DS was fully reproduced following gp160-recombination, while it was only partially reproduced following gp120- or gp41-recombination. The mutations in gp41 of NL4.3/SPL2923 were sufficient to reproduce the cross resistance to enfuvirtide. Unexpectedly, the reduced sensitivity towards SPL2923 was not fully reproduced after gp160-recombination. The search for mutations in NL4.3/SPL2923 in viral genes other than env revealed several mutations in the gene encoding the HIV p17 matrix protein (MA) and one mutation in the gene encoding the p24 capsid protein (CA). In order to analyse the impact of the gag mutations alone and in combination with the mutations in env on the phenotypic resistance towards SPL2923, we developed a novel p17- and p17/gp160-CVT. Phenotypic analysis of the NL4.3/SPL2923 p17- and p17/gp160-recombined strains indicated that the mutations in both env and gag have to be present to fully reproduce the resistance of NL4.3/SPL2923 towards SPL2923.

Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention.

Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.

Evidence of dual sites of action of dendrimers: SPL-2999 inhibits both virus entry and late stages of herpes simplex virus replication.

Dendrimers are macromolecules with broad-spectrum antiviral activity and minimal toxicity effective in animal models in preventing transmission of herpes simplex virus (HSV) infection. In order to further understand the mechanism of action, and toxicity profiles of the dendrimer SPL-2999 against HSV, we investigated in vitro activities as follows: modified plaque reduction assays for SPL-2999 showed that 50% effective concentrations (EC(50)) determined by pre-treatment of cells with SPL-2999 were 0.5 microg/ml (30 nM) for HSV-2 and 1 microg/ml (60 nM) for HSV-1, respectively. SPL-2999 was not toxic to Vero cells at concentration up to the highest tested (CC(50) greater than 1000 microg/ml). SPL-2999 appears to completely inhibit both viral adsorption and penetration to Vero cells at concentrations of higher than 3 microg/ml. Additionally, virus yield reduction assay showed that SPL-2999 was effective on cells already infected with HSV with EC(90)s (effective concentration giving 90% virus yield reduction) approximately 29.2 microg/ml for HSV-1 and 6.7 microg/ml for HSV-2. When Vero cells were infected with HSV at moi (multiplicity of infection) of 0.01 pfu/cell, the infected cells could be completely protected from viral cytopathic effect (CPE) by SPL-2999 with EC(90)s (effective concentration that protects 90% of cells from virus lysis) of 15 microg/ml for HSV-1 and 10 microg/ml for HSV-2. Results from Southern blot hybridization indicated that SPL-2999 inhibited DNA synthesis in HSV infected cells. We conclude that SPL-2999 inhibits both HSV entry into susceptible cells and late stages of HSV replication. Our data indicate that SPL-2999 is a potent inhibitor of both HSV-1 and -2 with the potential for further development as either a topical microbicide or a therapeutic agent.

Section 136 and African/Afro Caribbean minorities

Social, demographic and clinical information was collected retrospectively on all 99 people referred to a South London hospital in 1986 under Section 136 of the Mental Health Act (1983), this being the last complete year before local changes in the procedure for assessment of Section 136 cases were initiated. An over-representation of Afro-Caribbeans was confirmed and thia seemed to be accounted for largely by young men under the age of 30 who with Africans had very high rates of previous Section 136 referral, were more likely to be percieved as threatening, incoherent and disturbed but less clearly diagnosed with a mental illness, and were more likely than the Caucasian sample to be living in stable accommodation. The implications of these results are discussed. (Summary)