Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m²) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non–bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HR_KL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HR_KL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m², effects were strengthened (HR_KL<2 0.49 [95% CI, 0.26 to 0.92]; HR_KL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).     

KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.     

Evaluating the Efficacy of Photodynamic Therapy with 20% Aminolevulinic Acid and Microdermabrasion as a Combination Treatment Regimen for Acne Scarring: A Split-face,Randomized, Double-blind Pilot Study

Acne scarring is a consequence of abnormal resolution of wound healing after damage that occurs in the sebaceous follicle during acne inflammation. No trial to date has evaluated the efficacy of the combination of microdermabrasion and photodynamic therapy for acne scarring. This single-center, double-blinded pilot study enrolled subjects with moderate-to-severe acne scarring who were randomly assigned in a blinded fashion to use aminolevulinic acid and vehicle in a split-face fashion after full-face treatment with microdermabrasion. On average, 80 percent of the patients displayed more improvement in scarring on the aminolevulinic acid split face versus the vehicle split face after five treatments. Using two different noninvasive mechanisms of targeting acne scarring provided for a safe treatment regimen characterized by more efficacious results with respect to higher rates of scarring improvement.Acne affects nearly 80 percent of adolescents and young adults. A recent community-based study of close to 800 subjects reported the overall acne scarring prevalence to be 14 percent in women and 11 percent in men.1 Severe scarring caused by acne is associated with substantial physical and psychological distress and has been associated with poor self-esteem, emotional debilitation, and lowered academic performance.2Acne scarring is a consequence of abnormal resolution of wound healing after damage that occurs in the sebaceous follicle during acne inflammation.3 The cause is due to either increased formation of tissue (hypertrophic scars or keloids) or damage to tissue (ice pick, rolling, and boxcar scars), leaving atrophic scars. All types of acne, from papulopustular to nodulocystic disease, can cause scarring; therefore, adequate treatment must be started early.4 Of the therapeutic approaches available for acne scarring, microdermabrasion represents a noninvasive efficacious treatment for contour irregularities. A molecular trial showed that after a single microdermabrasion treatment, matrix metalloproteinases involved in dermal remodeling and wound healing were upregulated in the biopsies taken from subjects with severe acne scarring.5Photodynamic therapy (PDT) involves the topical administration of aminolevulinic acid (ALA) and has been successfully utilized as a noninvasive treatment modality for acne. While not photosensitive by itself, ALA is converted by keratinocytes to protoporphyrin IX, which is a photosensitive compound that is activated by a blue light source. The reactive oxygen species formed in this reaction produce beneficial immunological changes. In the murine contact hypersensitivity model, PDT-ALA was found to cause local immunosuppression by decreasing the number of epidermal Langerhans cells, a finding which suggests that PDT has a potential immunological contribution to clinical efficacy for inflammatory diseases.Additionally, PDT has been shown to stimulate various matrix metalloproteinases, which may explain the collagen remodeling produced by this method. The side effect profile of topical ALA-PDT is extremely favorable, with mild pain and temporary cutaneous photosensitivity reported as the most frequent documented adverse effects. Many studies concerning the anti-inflammatory effects of PDT on acne have been published; however, a study specifically focusing on the use of PDT for acne scarring has yet to be conducted.No trial to date has evaluated the efficacy of the combination of microdermabrasion and ALA-PDT for acne scarring. However, targeting acne scarring with microdermabrasion followed by ALA-PDT appears to be logical. The authors hypothesize that the ability to increase the permeability barrier via the use of microdermabrasion will enhance the absorption of 5-ALA and thereby increase the efficacy of the combination treatment for acne scarring. They also hypothesize that utilizing microdermabrasion prior to application of ALA will speed the acid’s absorption, shortening the incubation time needed to 60 minutes, which could greatly enhance both patient convenience and physician productivity.The efficacy of the combination procedure may provide for a faster, yet longer-sustained clearance effect. In summary, by using two different mechanisms of targeting acne scarring, the authors expect to have more efficacious results with respect to higher rates of scarring improvement. They also hope to bring to the forefront a new therapeutic regimen for acne scarring, which combines two provider-applied modalities.     

Real-world Evidence for the Antianginal Efficacy of Trimetazidine from the Russian Observational CHOICE-2 Study

Introduction

The guidelines recommend a beta-blocker or calcium channel blocker as the first-line medication for angina, supplemented by other agents for additional symptoms. One such agent is trimetazidine (TMZ), which has been shown to reduce the frequency of anginal episodes and improve exercise performance without affecting haemodynamic parameters. However, extensive real-world evidence for its efficacy in combination with first-line therapies has been lacking.

Methods

The aim of this large-scale, Russian, multicentre, 6-month, open-label, prospective observational study was to assess the effect of adding TMZ modified release 35 mg bid to background antianginal therapy in the real-world clinical setting.

Results

The study included 896 patients: 54% women, aged 29–90 years (42.6% >65 years), 63% with class II angina, and receiving beta-blockers alone or in combination (93%). Add-on TMZ reduced angina frequency and short-acting nitrate use within 2 weeks (both p < 0.0001) regardless of background therapy and maintained this effect over 6 months. It increased the proportion of patients with class I angina sixfold while decreasing that of class 3 angina almost fourfold. It also improved walking distance and well-being at 6 months (both p < 0.0001). Treatment was well tolerated.

Conclusion

Add-on TMZ is a safe and rapidly effective treatment for reducing angina attacks and nitrate use in the real-world clinical setting. It also increases exercise capacity and well-being. These effects are observed within 2 weeks and persist for at least 6 months.

     

Sulodexide in Patients with Chronic Venous Disease of the Lower Limbs: Clinical Efficacy and Impact on Quality of Life

Introduction

Chronic venous disease (CVD) of the lower limbs is a common problem. It is more prevalent in women than in men and has a significant impact on patients’ quality of life (QoL) and on the healthcare system. The aim of this study was to evaluate the efficacy of sulodexide in adult patients with CVD of the lower limbs and its effect on patients’ QoL.

Methods

Patients with CVD were treated with sulodexide [250 LSU (lipasemic units) twice daily] for 3 months in a setting of real-life clinical practice. The endpoints of this observational non-comparative, open-label prospective study were the clinical efficacy of sulodexide (evaluated by scoring objective and subjective symptoms with a Likert-type scale) and the impact of sulodexide therapy on patients’ QoL [assessed using the chronic venous insufficiency quality of life questionnaire (CIVIQ)].

Results

The study included 450 patients (mean age 46.9 ± 10.5 years, range 17–78 years). A greater percentage of patients were female (65.4%). Three months of treatment with sulodexide significantly improved all objective and subjective symptoms (p < 0.0001). Overall, patients reported a significant improvement in all QoL scores (p < 0.0001). Adverse events were spontaneously reported by two patients (one case of epigastric pain and one of gastric pain with vomiting).

Conclusion

Oral sulodexide significantly improves both objective and subjective symptoms, as well as functional and psychological aspects of QoL in patients with CVD.

Funding

No funding or sponsorship was received for this study. Sponsorship for article processing charges and open access fees was provided by Alfa Wassermann.

     

Determinants of mitotic catastrophe on abrogation of the G2 DNA damage checkpoint by UCN-01

Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G(2) DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass the checkpoint and induce unscheduled mitosis in irradiated cells. Precisely, how cells behave following checkpoint abrogation remains to be defined. In this study, we tracked the fates of individual cells after checkpoint abrogation, focusing in particular on whether they undergo mitotic catastrophe. Surprisingly, while a subset of UCN-01-treated cells were immediately eliminated during the first mitosis after checkpoint abrogation, about half remained viable and progressed into G(1). Both the delay of mitotic entry and the level of mitotic catastrophe were dependent on the dose of radiation. Although the level of mitotic catastrophe was specific for different cell lines, it could be promoted by extending the mitosis. In supporting this idea, weakening of the spindle-assembly checkpoint, by either depleting MAD2 or overexpressing the MAD2-binding protein p31(comet), suppressed mitotic catastrophe. Conversely, delaying of mitotic exit by depleting either p31(comet) or CDC20 tipped the balance toward mitotic catastrophe. These results underscore the interplay between the level of DNA damage and the effectiveness of the spindle-assembly checkpoint in determining whether checkpoint-abrogated cells are eliminated during mitosis.     

Effects of Ramadan fasting on platelet reactivity in diabetic patients treated with clopidogrel

Background

The effects of Ramadan fasting (RF) on clopidogrel antiplatelet inhibition were not previously investigated. The present study evaluated the influence of RF on platelet reactivity in patients with high cardiovascular risk (CVR) in particular those with type 2 diabetes mellitus (DM).

Methods

A total of 98 stable patients with ≥2 CVR factors were recruited. All patients observed RF and were taking clopidogrel at a maintenance dose of 75 mg. Clinical findings and serum lipids data were recorded before Ramadan (Pre-R), at the last week of Ramadan (R) and 4 weeks after the end of Ramadan (Post-R). During each patient visit, nutrients intakes were calculated and platelet reactivity assessment using Verify Now P2Y12 assay was performed.

Results

In DM patients, the absolute PRU changes from baseline were +27 (p = 0.01) and +16 (p = 0.02) respectively at R and Post-R. In addition, there was a significant increase of glycemia and triglycerides levels with a significant decrease of high-density lipoprotein. In non DM patients there was no significant change in absolute PRU values and metabolic parameters. Clopidogrel resistance rate using 2 cut-off PRU values (235 and 208) did not change significantly in DM and non DM patients.

Conclusions

RF significantly decreased platelet sensitivity to clopidogrel in DM patients during and after Ramadan. This effect is possibly related to an increase of glycemia and serum lipids levels induced by fasting.

Trial registration

Clinical Trials.gov NCT02720133. Registered 24 July 2014.Retrospectively registered.

     

Impact of Trauma System Structure on Injury Outcomes: A Systematic Review and Meta-Analysis

Background

The effectiveness of trauma systems in decreasing injury mortality and morbidity has been well demonstrated. However, little is known about which components contribute to their effectiveness. We aimed to systematically review the evidence of the impact of trauma system components on clinically important injury outcomes.

Methods

We searched MEDLINE, EMBASE, Cochrane CENTRAL, and BIOSIS/Web of Knowledge, gray literature and trauma association Web sites to identify studies evaluating the association between at least one trauma system component and injury outcome. We calculated pooled effect estimates using inverse-variance random-effects models. We evaluated quality of evidence using GRADE criteria.

Results

We screened 15,974 records, retaining 41 studies for qualitative synthesis and 19 for meta-analysis. Two recommended trauma system components were associated with reduced odds of mortality: inclusive design (odds ratio [OR] = 0.72 [0.65–0.80]) and helicopter transport (OR = 0.70 [0.55–0.88]). Pre-Hospital Advanced Trauma Life Support was associated with a significant reduction in hospital days (mean difference [MD] = 5.7 [4.4–7.0]) but a nonsignificant reduction in mortality (OR = 0.78 [0.44–1.39]). Population density of surgeons was associated with a nonsignificant decrease in mortality (MD = 0.58 [?0.22 to 1.39]). Trauma system maturity was associated with a significant reduction in mortality (OR = 0.76 [0.68–0.85]). Quality of evidence was low or very low for mortality and healthcare utilization.

Conclusions

This review offers low-quality evidence for the effectiveness of an inclusive design and trauma system maturity and very-low-quality evidence for helicopter transport in reducing injury mortality. Further research should evaluate other recommended components of trauma systems and non-fatal outcomes and explore the impact of system component interactions.