Strongyloides stercoralis hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with S. stercoralis, we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in S. stercoralis-infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with Δ7-dafachronic acid, an agonist of the parasite nuclear receptor Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with S. stercoralis Overall, this study provides a useful mouse model for S. stercoralis autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.

To our knowledge, the comparative effectiveness of commonly used conservative treatments for carpal tunnel syndrome has not been evaluated previously in primary care. We aimed to compare the clinical and cost-effectiveness of night splints with a corticosteroid injection with regards to reducing symptoms and improving hand function in patients with mild or moderate carpal tunnel syndrome.

We did this randomised, open-label, pragmatic trial in adults (≥18 years) with mild or moderate carpal tunnel syndrome recruited from 25 primary and community musculoskeletal clinics and services. Patients with a new episode of idiopathic mild or moderate carpal tunnel syndrome of at least 6 weeks' duration were eligible. We randomly assigned (1:1) patients (permutated blocks of two and four by site) with an online web or third party telephone service to receive either a single injection of 20 mg methylprednisolone acetate (from 40 mg/mL) or a night-resting splint to be worn for 6 weeks. Patients and clinicians could not be masked to the intervention. The primary outcome was the overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks. We used intention-to-treat analysis, with multiple imputation for missing data, which was concealed to treatment group allocation. The trial is registered with the European Clinical Trials Database, number 2013-001435-48, and ClinicalTrial.gov, number NCT02038452.

Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2·02 [SD 0·81]) than the night splint group (2·29 [0·75]; adjusted mean difference -0·32; 95% CI -0·48 to -0·16; p=0·0001). No adverse events were reported.

A single corticosteroid injection shows superior clinical effectiveness at 6 weeks compared with night-resting splints, making it the treatment of choice for rapid symptom response in mild or moderate carpal tunnel syndrome presenting in primary care.

Arthritis Research UK.

BACKGROUND

The treatment of postherpetic neuralgia (PHN) continues to be a challenge in clinical pain management. In this randomized, controlled study, we assessed the effectiveness of repetitive paravertebral injections with local anesthetics and steroids for the prevention of PHN in patients with acute herpes zoster.

METHODS

One hundred thirty-two patients with acute herpes zoster diagnosed 1-7 days after the onset of the rash were randomly assigned to receive either standard therapy (oral antivirals and analgesics) or standard therapy with additional repetitive paravertebral injections of a mixture of 10 mL 0.25% bupivacaine and 40 mg methylprednisolone acetate every 48 h for a week. Efficacy was evaluated at 1, 3, 6, and 12 mo after the end of the treatments. The primary end point was the proportion of patients with zoster-associated pain and/or allodynia 1 mo after inclusion. Statistical analysis was performed based on the intent-to-treat population.

RESULTS

One hundred thirteen patients completed the 1-yr follow-up. At 1 mo posttherapy, 13% of patients in the paravertebral group reported zoster-related pain, compared with 45% in the standard group (P < 0.001). At 3, 6, and 12 mo posttherapy, the incidence of PHN was still significantly lower in the paravertebral group than in the standard group. The quality of life improved in both groups at each follow-up time point with no significant difference between groups.

CONCLUSIONS

Repetitive paravertebral anesthetic block in combination with steroids plus standard treatment with acyclovir and analgesics significantly reduced the incidence of PHN than the standard treatment alone.

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 hours in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

Background: There are limited data discussing long-term pain relief and comparability of different image-guided sacroiliac joint (SIJ) injection. This study compared CT and fluoroscopic-guided SIJ injections regarding statistically and clinically significant differences in numeric pain reduction, radiation doses, and patient's satisfaction.

Methods: A prospective study conducted on 52 patients who met specific inclusion criteria of SIJ pain. A mixture of 1 ml of 40 mg methylprednisolone acetate diluted in 2 ml of lidocaine 2% was injected under either CT or fluoroscopic guidance. Numeric rating score (NRS) and Oswestry disability index (ODI) were assessed and recorded for each patient before procedure and one-week, and one-, three-, six-, and 12-months after procedure. The results were compared between both groups.

Results: Analysis of NRS one-month post-procedure showed a significant decrease from baseline in both groups: 12.5% in CT group (p = 0.002) and 9.5% in fluoroscopic group (p = 0.006). No significant difference in NRS between two groups at one- and three-months post-procedure (p = 0.11 and 0.1, respectively). There was a significant difference in NRS between two groups at six- and 12-months post-procedure (p = 0.001 and < 0.0001, respectively). Comparison of ODI at six-month post-procedure revealed that both groups had a statistically significant improvement (p < 0.0001). There was a significant difference in ODI between two groups at six-months post-procedure (p = 0.01).

Conclusions: CT-guided SIJ injection compares favorably with fluoroscopic guidance and offers statistically and clinically significant long-term pain relief. The use of dose reduction protocol in CT is important for decreasing the radiation dose.

Keywords: Computed tomography; Fluoroscopy; Pain management; Sacroiliac joint pain.

Primary deep digital flexor tendon (DDFT) pathologies and those accompanying degenerative changes of navicular bone fibrocartilage are major causes of lameness associated with navicular disease. Intrasynovial corticosteroids are mainstay in the treatment due to the anti-inflammatory effects, but their effect on DDFT cell biosynthesis are unknown. The objective of this in-vitro study was to investigate the effects of methylprednisolone acetate (MPA) on cells isolated from the dorsal fibrocartilaginous region of forelimb DDFTs (DDFT-derived cells) of 5 horses (aged 11-17 years). Non-adherent aggregate cultures were established from third passage cells over a 72 to 96-h duration prior to treating with medium containing 0 (control), 0.05 and 0.5 mg/mL MPA for 24 h. Tendon and cartilage extracellular matrix (ECM) related gene expression, cell aggregate and culture medium GAG contents, culture medium collagen and MMP-3 and-13 concentrations were measured. After 24 h of treatment, only the higher MPA concentration (0.5 mg/mL) significantly down-regulated tendon ECM related genes; whereas, both MPA doses significantly down-regulated cartilage ECM related genes. MPA treatment did not affect the total GAG content of DDFT-derived cells or total GAG, soluble collagen and MMP-3 and-13 contents in culture medium compared to untreated controls. Future studies to determine the response of DDFT-derived cells with longer exposure times to corticosteroids and in the presence of inflammatory cytokines are necessary. These results are a first step in assessing the effects of intrasynovial medications on equine DDFT, for which currently no information exists.

Keywords: ECM mRNA expression; GAG; MMP-3/-13; collagen; deep digital flexor tendon; horse; methylprednisolone acetate; navicular disease.

OBJECTIVE To compare the effects of 3 equimolar concentrations of methylprednisolone acetate (MPA), triamcinolone acetonide (TA), and isoflupredone acetate (IPA) on equine articular tissue cocultures in an inflammatory environment. SAMPLE Synovial and osteochondral explants from the femoropatellar joints of 6 equine cadavers (age, 2 to 11 years) without evidence of musculoskeletal disease. PROCEDURES From each cadaver, synovial and osteochondral explants were harvested from 1 femoropatellar joint to create cocultures. Cocultures were incubated for 96 hours with (positive control) or without (negative control) interleukin (IL)-1β (10 ng/mL) or with IL-1β and MPA, TA, or IPA at a concentration of 10-4, 10-7, or 10-10M. Culture medium samples were collected from each coculture after 48 and 96 hours of incubation. Concentrations of prostaglandin E2, matrix metalloproteinase-13, lactate dehydrogenase, and glycosaminoglycan were determined and compared among treatments at each time. RESULTS In general, low concentrations (10-7 and 10-10M) of MPA, TA, and IPA mitigated the inflammatory and catabolic (as determined by prostaglandin E2 and matrix metalloproteinase-13 quantification, respectively) effects of IL-1β in cocultures to a greater extent than the high (10-4M) concentration. Mean culture medium lactate dehydrogenase concentration for the 10-4M IPA treatment was significantly greater than that for the positive control at both times, which was suggestive of cytotoxicosis. Mean culture medium glycosaminoglycan concentration did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the in vitro effects of IPA and MPA were similar to those of TA at clinically relevant concentrations (10-7 and 10-10M).

Background and aims: Coccygodynia or Coccydynia is pain in the area of coccyx and ganglion impar block is commonly used technique for treatment of coccygodynia.

Material and methods: Forty patients of either sex in the age group of 20-70 years suffering from coccygodynia, who failed to respond to six weeks of conservative treatment were enrolled in the study. All patients were subjected to detailed clinical history, examination in the Pain Management Centre (Pain Clinic) of our Institute and imaging studies were reviewed. The patients were randomly divided into two groups of 20 each by a computer generated randomization number table: Group-TS (n = 20): Patients were administered ganglion Impar block by trans-sacrococcygeal approach Group-TC (n = 20): Patients were administered ganglion Impar block by trans-coccygeal approach with 8 ml of 0.5% bupivacaine plus 2 ml of 40mg/ml methylprednisolone acetate under fluoroscopic guidance.

Results: Both the techniques of ganglion Impar block were effective and provided good pain relief to the patients with coccygodynia. There was a statistically and clinically significant improvement in pain score after ganglion Impar block in both the groups at all time intervals during the study period. (p < 0.05). The mean pain score after ganglion Impar block was <2 at all time intervals throughout the three month study period in all patients in the two groups. All patients in both the groups had excellent satisfaction immediately after ganglion Impar block. Five patients each in both groups required second ganglion Impar block during the three months study period.

Conclusion: Both trans-sacrococcygeal and trans-coccygeal approaches of ganglion Impar block with a combination of local anaesthetic and steroid are safe and effective for management of coccygodynia. Trans-coccygeal ganglion Impar block through the first intra-coccygeal joint is better in terms of improvement in pain score, functional disability, patient satisfaction and ease of administration.

Keywords: Coccygodynia; ganglia impar block; transcoccygeal approach; transsacrococcygeal approach.

Background: Interlaminar epidural steroid injection (ILESI) is commonly performed nonsurgical intervention in patients with lumbar spinal stenosis. There is no consensus regarding appropriate intervertebral level of ILESI that leads to maximum effectiveness. In this study, we compared the efficacy of ILESI on pain relief and functional improvement when given at the level of maximum stenosis versus at nearby less stenotic levels in patients of lumbar canal stenosis.

Materials and methods: In this study, 80 patients were randomly allocated to two groups: Group A received lumbar ILESI of 5mL bupivacaine (0.25%), 2 mL methylprednisolone acetate (40 mg/mL), and 1 mL normal saline at maximal stenotic intervertebral level, and Group B received the same drugs at less stenotic level, two intervertebral spaces cephalad or caudad to maximum stenosis. The effects were evaluated by Numeric Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI) at 2, 6, and 12 weeks after the intervention.

Results: Results of 30 patients in each group were assessed. Pain relief and improvement in ODI were observed in both groups after injection. Group A had significantly better pain relief at 2 and 4 weeks after injection. The ODI at 2, 6, and 12 weeks after injection was significantly lower in Group A as compared to Group B.

Conclusion: ILESI at maximum stenotic intervertebral level leads to better pain relief and functional improvement as compared to injection given at less stenotic level in lumbar spinal canal stenosis.

Keywords: Epidural injection; low back pain; lumbar spinal stenosis; steroid.

The use of intra-articular corticosteroids for traumatic arthritis and osteoarthritis (OA) is common in the horse. The beneficial and deleterious effects of the principal corticosteroids used betamethasone esters (Celestone [Soluspan], methylprednisolone acetate [Depo Medrol], and triamcinolone acetonide [TA] [Vetalog or Kenalog]) have been defined for the horse. While TA has both disease-modifying as well as symptom-modifying effects, methyl prednisolone acetate has deleterious effects on the articular cartilage. Studies in traumatically injured joints show the same rationale (suppression of deleterious mediators associated with inflammation) and positive results from the use of TA in both equine and human patients. Studies in the experimental equine OA model allow for more in-depth knowledge of disease-modifying effects. Recent insights allow us to understand posttraumatic OA as an early consequence of joint injury that may require a more aggressive and proactive treatment approach than commonly applied to date.

Importance: There is an unprecedented need to rapidly identify safe and effective treatments for the novel coronavirus disease 2019 (COVID-19). Objective: To systematically investigate if any of the available drugs in Electronic Health Record (EHR), including prescription drugs and dietary supplements, can be repurposed as potential treatment for COVID-19. Design, Setting, and Participants: Based on a retrospective cohort analysis of EHR data, drug-wide association studies (DrugWAS) were performed on COVID-19 patients at Vanderbilt University Medical Center (VUMC). For each drug study, multivariable logistic regression with overlap weighting using propensity score was applied to estimate the effect of drug exposure on COVID-19 disease outcomes. Exposures: Patient exposure to a drug during 1-year prior to the pandemic and COVID-19 diagnosis was chosen as exposure of interest. Natural language processing was employed to extract drug information from clinical notes, in addition to the prescription drug data available in structured format. Main Outcomes and Measures: All-cause of death was selected as primary outcome. Hospitalization, admission to the intensive care unit (ICU), and need for mechanical ventilation were identified as secondary outcomes. Results: The study included 7,768 COVID-19 patients, of which 509 (6.55%) were hospitalized, 82 (1.06%) were admitted to ICU, 64 (0.82%) received mechanical ventilation, and 90 (1.16%) died. Overall, 15 drugs were significantly associated with decreased COVID-19 severity. Previous exposure to either Streptococcus pneumoniae vaccines (adjusted odds ratio [OR], 0.38; 95% CI, 0.14-0.98), diphtheria toxoid vaccine (OR, 0.39; 95% CI, 0.15-0.98), and tetanus toxoid vaccine (OR, 0.39; 95% CI, 0.15-0.98) were significantly associated with a decreased risk of death (primary outcome). Secondary analyses identified several other significant associations showing lower risk for COVID-19 outcomes: 2 vaccines (acellular pertussis, Streptococcus pneumoniae), 3 dietary supplements (turmeric extract, flaxseed extract, omega-3 fatty acids), methylprednisolone acetate, pseudoephedrine, ethinyl estradiol, estradiol, ibuprofen, and fluticasone. Conclusions and Relevance: This cohort study leveraged EHR data to identify a list of drugs that could be repurposed to improve COVID-19 outcomes. Further randomized clinical trials are needed to investigate the efficacy of the proposed drugs.