Azithromycin SR versus minocycline in the treatment of moderate to severe acne: a phase III, multicentre, randomized, non-inferiority trial

Introduction: The primary objective of this phase III, multicentre, randomized trial was to evaluate whether azithromycin SR (azithromycin microspheres, powder for oral suspension) was non-inferior to oral minocycline in the treatment of moderate to severe acne. The primary efficacy endpoint was the change from baseline in the GAGS score. Secondary endpoints included changes from baseline in the Leeds score and quality of life (QoL). Methods: A total of 118 patients were randomized (1:1) to receive azithromycin SR (2 g/week) (n = 58) or minocycline (100 mg q.d.) (n = 60) for eight weeks. Results: The change from baseline to end of treatment in GAGS score did not differ significantly between the azithromycin SR and minocycline groups [least squares mean -8.69 (95% confidence interval [CI]: -10.33 to -7.05) and -9.16 (95% CI: -10.62 to -7.71), respectively], consistent with the noninferiority of azithromycin SR to minocycline. The lower limit of 95% confidence interval of the change from baseline to end of treatment in GAGS scores between the 2 groups (95% CI: -2.48 to 1.54) did not exceed the pre-defined non-inferiority margin of -3. In addition, there were no significant differences in improvement of acne graded by the Leeds score and QoL. Twenty-six patients (44.8%) in the azithromycin SR group and 9 patients (15%) in the minocycline group reported gastro-intestinal disorders. Conclusions: In patients with moderate to severe acne, azithromycin SR is non-inferior to minocycline for primary endpoint (GAGS score), with no significant differences in secondary endpoints

Extended thromboprophylaxis with betrixaban in acutely ill medical patients

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.)

Clindamycin phospate-zinc acetate versus clindamycin phosphate-zinc acetate + adapalene in the treatment of mild to moderate acne. Results of a multicentre, randomized, retrospective, sponsor-free study

Introduction: The aim of the present study was to evaluate the efficacy and the response in patients with mild to moderate acne of a clindamycin phosphate-zinc acetate topical therapy in comparison with clindamycin phosphate-zinc acetate plus adapalene. Methods: Patients with mild to moderate acne were randomized into two groups and treated, respectively, with a gel containing 1 % clindamycin phosphate-0.5% zinc acetate (2 applications/day for 12 weeks) or with the same gel (1 application/day for 12 weeks) plus a gel containing 0.1% adapalene (1 application/day for 12 weeks). No other topical or systemic drugs were allowed, except for a detergent and a sunscreen. Acne severity and treatment efficacy were evaluated by means of the Global Acne Grading System (GAGS). Results: At the end of the study, 63 patients were considered evaluable (29 patients in the group treated with clindamycin-zinc and 34 in the group treated with clindamycin-zinc and adapalene). Significant clinical improvement (maggiore/uguale 50% from baseline) was observed in 12/29 patients (41.4%) in the group treated with clindamycin-zinc and in 22/34 patients (64.7%) in the group treated with clindamycin-zinc and adapalene (p< 0.05). Irritant contact dermatitis was observed in 12 patients (3 in the group treated with clindamycin-zinc and 9 in the group treated with clindamycin-zinc and adapalene); in the latter group, two patients stopped the treatment. Conclusions: On the basis of the results of this study, which is the first one on the activity and tolerability of the association clindamycin-zinc, the latter association is less effective than the association clindamycin-zinc and adapalene

Prevention of relapses in patients previously treated with oral isotretinoin for severe acne. Results of a multicentre, randomized, retrospective, sponsor-free study

Introduction: After a systemic treatment with oral isotretinoin, acne therapy must be continued with topical products in order to avoid possible relapses. The aim of this study was to assess whether a topical retinoid is an effective choice in the prevention of relapses. Methods: Patients who were successfully treated with oral isotretinoin for severe acne, at the end of the therapy were randomized into two groups: the first one was treated with a topical retinoid (0.05% tretinoin or 0.05% isotretinoin or 0.1 % adapalene, 1 application/day for 6-8 months); the second group was not treated (only detergents and moisturizers were allowed). Follow up was >6 months. Results: At the end of the study, 2/37 patients (5.4%) treated with topical retinoids developed a relapse; in the group of patients who were not treated, 7/31 patients (22.6%) developed a relapse (p< 0.05). Conclusions: On the basis of the results of this study, topical retinoids are helpful in the prevention of relapses of acne in patients previously treated with oral isotretinoin

History of migraine and volume of brain infarcts: The italian project on stroke at young age (IPSYS)

BACKGROUND AND PURPOSE: Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. METHODS: In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. RESULTS: A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P<0.001), and the largest volumes were observed in patients with migraine with aura (median, 9.0 cm3 [IQR, 3.4 to 16.6]). In a linear regression model, migraine was an independent predictor of increased log (acute infarct volumes) (median ratio [MR], 1.64; 95% confidence interval [CI], 1.22 to 2.20), an effect that was more prominent for migraine with aura (MR, 2.92; 95% CI, 1.88 to 4.54). CONCLUSION: s These findings reinforce the experimental observation of larger acute cerebral infarcts in migraineurs, extend animal data to human disease, and support the hypothesis of increased vulnerability to ischemic brain injury in people suffering migraine

Preoperative Magnetic Resonance and Intraoperative Ultrasound Fusion Imaging for Real-Time Neuronavigation in Brain Tumor Surgery = Pr&#228;operative MRI- und intraoperative Ultraschallfusion f&#252;r die Echtzeit-Neuronavigation in der Neurochirurgie von Hirntumoren

Purpose: Brain shift and tissue deformation during surgery for intracranial lesions are the main actual limitations of neuro-navigation (NN), which currently relies mainly on preoperative imaging. Ultrasound (US), being a real-time imaging modality, is becoming progressively more widespread during neurosurgical procedures, but most neurosurgeons, trained on axial computed tomography (CT) and magnetic resonance imaging (MRI) slices, lack specific US training and have difficulties recognizing anatomic structures with the same confidence as in preoperative imaging. Therefore real-time intraoperative fusion imaging (FI) between preoperative imaging and intraoperative ultrasound (ioUS) for virtual navigation (VN) is highly desirable. We describe our procedure for real-time navigation during surgery for different cerebral lesions. Materials and Methods: We performed fusion imaging with virtual navigation for patients undergoing surgery for brain lesion removal using an ultrasound-based real-time neuro-navigation system that fuses intraoperative cerebral ultrasound with preoperative MRI and simultaneously displays an MRI slice coplanar to an ioUS image. Results: 58 patients underwent surgery at our institution for intracranial lesion removal with image guidance using a US system equipped with fusion imaging for neuro-navigation. In all cases the initial (external) registration error obtained by the corresponding anatomical landmark procedure was below 2mm and the craniotomy was correctly placed. The transdural window gave satisfactory US image quality and the lesion was always detectable and measurable on both axes. Brain shift/deformation correction has been successfully employed in 42 cases to restore the co-registration during surgery. The accuracy of ioUS/MRI fusion/overlapping was confirmed intraoperatively under direct visualization of anatomic landmarks and the error was < \u30083mm in all cases (100%). Conclusion: Neuro-navigation using intraoperative US integrated with preoperative MRI is reliable, accurate and user-friendly. Moreover, the adjustments are very helpful in correcting brain shift and tissue distortion. This integrated system allows true real-time feedback during surgery and is less expensive and time-consuming than other intraoperative imaging techniques, offering high precision and orientation.Brain Shift und Gewebeverschiebung w\ue4hrend der chirurgischen Entfernung intrakranialer Raumforderungen sind die limitierenden Faktoren bei der Neuronavigation (NN), welche aktuell haupts\ue4chlich pr\ue4operative Bilder einsetzt. Ultraschall (US) als Echtzeit-Bildgebung wird bei neurochirurgischen Prozeduren zunehmend angewandt. Vielen Neurochirurgen fehlt aber die US Expertise, da schon in der Ausbildung standarisierte (typisch axiale) CT und MRT Schnittbilder f\ufcr die Navigation bevorzugt eingesetzt werden und somit die Sicherheit bei der sonografischen Identifikation anatomischer Strukturen fehlt. Daher ist eine intraoperative Echtzeitfusion zwischen pr\ue4operativen CT bzw. MRT Bildern und intraoperativem Ultraschall (ioUS) im Rahmen der virtuellen Navigation (VN) au ferordentlich w\ufcnschenswert. Wir pr\ue4sentieren hier die bei uns angewandte Methode f\ufcr dieEchtzeitnavigation bei der Entfernung verschiedener Hirntumoren. Material und Methoden: Wir wandten die Bildfusion mit virtueller Navigation bei der chirurgischen Entfernung von Hirntumoren an. Zum Einsatz kam ein Neuronavigationssystem, welches intraoperative Ultraschallbilder mit pr\ue4operativen MRT Bildern in Echtzeit \ufcberlagert und zu jedem US Bild simultan die dazu passende ko-planare MRTSchnittebene anzeigt. Ergebnisse: Die US-basierte Neuronavigation wurde bei der Operation von 58 Patienten mit Hirntumoren eingesetzt. In allen F\ue4llen war der Fehler der initialen (externen) Registrierung, welche anhand von anatomischen Landmarken erfolgte, unterhalb von 2mm und die Kraniotomie konnte korrekt angesetzt werden. Die Bildqualit\ue4t des transduralen Ultraschalls war gut und die L\ue4sion konnte bei allen Patienten detektiert und in allen Achsen vermessen werden. Die Korrektur von Brain Shift sowie Gewebeverschiebung gelang erfolgreich in 42 F\ue4llen zur Wiederherstel lung der intraoperativen Co-Registrierung. Die Genauigkeit der cberlagerung von ioUS und MRT wurde intraoperativ anhand der Visualisierung anatomischerLandmarken \ufcberpr\ufcft und der Fehler lag in allen F\ue4llen (100 %) unterhalb von 3mm. Schlussfolgerung: Neuronavigation mit Hilfe von in pr\ue4operative MRT Bilder integrierten intraoperativen US Bildern ist eine zuverl\ue4ssige, genaue und anwenderfreundliche neue Technologie. Brain Shift und Gewebeverlagerungen k\uf6nnen anhand verschiedener Einstellungsm\uf6glichkeiten am System erfolgreich intraoperativ korrigiert werden. Das integrierte System erm\uf6glicht eine intraoperative cberpr\ufcfung der Navigation in Echtzeit und ist dabei kosteng\ufcnstiger und weniger Zeit aufw\ue4ndig als andere intraoperative Bild-gebende Verfahren, trotzdem aber hoch pr\ue4zise

Interaction between proatherosclerotic factors and right-to-left shunt on the risk of cryptogenic stroke: the Italian Project on Stroke in Young Adults.

Objective: To explore the interaction effects between cardiac interatrial right-to-left shunt (RLS) and proatherosclerotic factors on the risk of brain ischaemia. Design: Multicentre Italian caseecontrol study. Setting: University hospitals. Participants: 588 patients with cryptogenic stroke (CS) aged ≤45 years and 585 control subjects consecutively enrolled as part of the Italian Project on Stroke in Young Adults. Methods: Interaction effects between RLS and an individual proatherosclerotic score computed from the number of conventional vascular risk factors for the risk of CS were investigated. Data were examined by logistic regression models and expressed as interaction OR or interaction risk difference (RD). Results: CS risk increased with increasing number of proatherosclerotic factors in subjects without RLS (OR 2.73; 95% CI 1.98 to 3.76; RD +0.246; 95% CI +0.17 to +0.32; for subjects with one or more factors), but was higher in subjects with RLS and no additional proatherosclerotic factors (OR 5.14; 95% CI 3.49 to 7.58; RD +0.388; 95% CI +0.31 to +0.47) compared with subjects without RLS and no risk factors. Negative interaction and antagonistic effects between RLS and proatherosclerotic factors were observed (interaction OR 0.52; 95% CI 0.31 to 0.91; interaction RD -0.17; 95% CI -0.29 to -0.05). Conclusions: The influence of RLS on the risk of CS decreases with increasing number of atherosclerotic factors, and is highest when such factors are absent. Individual proatherosclerotic profiles may help to identify patients with CS whose patent foramen ovale is probably pathogenic

Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: a systematic review and meta-analysis

Many aspects of care such as management of hypercoagulable state in COVID-19 patients, especially those admitted to intensive care units is challenging in the rapidly evolving pandemic of novel coronavirus disease 2019 (COVID-19). We seek to systematically review the available evidence regarding the anticoagulation approach to prevent venous thromboembolism (VTE) among COVID-19 patients admitted to intensive care units. Electronic databases were searched for studies reporting venous thromboembolic events in patients admitted to the intensive care unit receiving any type of anticoagulation (prophylactic or therapeutic). The pooled prevalence (and 95% confidence interval [CI]) of VTE among patients receiving anticoagulant were calculated using the random-effects model. Subgroup pooled analyses were performed with studies reported prophylactic anticoagulation alone and with studies reported mixed prophylactic and therapeutic anticoagulation. We included twelve studies (8 Europe; 2 UK; 1 each from the US and China) in our systematic review and meta-analysis. All studies utilized LMWH or unfractionated heparin as their pharmacologic thromboprophylaxis, either prophylactic doses or therapeutic doses. Seven studies reported on the proportion of patients with the previous history of VTE (range 0–10%). The pooled prevalence of VTE among ICU patients receiving prophylactic or therapeutic anticoagulation across all studies was 31% (95% CI 20–43%). Subgroup pooled analysis limited to studies reported prophylactic anticoagulation alone and mixed (therapeutic and prophylactic anticoagulation) reported pooled prevalences of VTE of 38% (95% CI 10–70%) and 27% (95% CI 17–40%) respectively. With a high prevalence of thromboprophylaxis failure among COVID-19 patients admitted to intensive care units, individualised rather than protocolised VTE thromboprophylaxis would appear prudent at interim