Hospital Universitario Fundación Alcorcón

BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concentration, and function of those components in the human body, particularly during pathological events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochemical analysis in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-associated astrocytes and microglia, respectively, whereas the expression of CB1 receptors remains unchanged. In addition, the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response associated with this neurodegenerative process and as possible targets for new therapeutic approaches.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after cardiac and major non-cardiac surgery with general anaesthesia in the elderly. We hypothesized that the incidence of POCD would be less with regional anaesthesia rather than general. METHODS: We included patients aged over 60 years undergoing major non-cardiac surgery. After giving written informed consent, patients were randomly allocated to general or regional anaesthesia. Cognitive function was assessed using four neuropsychological tests undertaken preoperatively and at 7 days and 3 months postoperatively. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in two or more test parameters. RESULTS: At 7 days, POCD was found in 37/188 patients (19.7%, [14.3-26.1%]) after general anaesthesia and in 22/176 (12.5%, [8.0-18.3%]) after regional anaesthesia, P = 0.06. After 3 months, POCD was present in 25/175 patients (14.3%, [9.5-20.4%]) after general anaesthesia vs. 23/165 (13.9%, [9.0-20.2%]) after regional anaesthesia, P = 0.93. The incidence of POCD after 1 week was significantly greater after general anaesthesia when we excluded patients who did not receive the allocated anaesthetic: 33/156 (21.2%[15.0-28.4%]) vs. 20/158 (12.7%[7.9-18.9%]) (P = 0.04). Mortality was significantly greater after general anaesthesia (4/217 vs. 0/211 (P < 0.05)). CONCLUSION: No significant difference was found in the incidence of cognitive dysfunction 3 months after either general or regional anaesthesia in elderly patients. Thus, there seems to be no causative relationship between general anaesthesia and long-term POCD. Regional anaesthesia may decrease mortality and the incidence of POCD early after surgery.

BACKGROUND: It is known that mortality after hip fracture increases compared to the general population; the trend in mortality is a controversial issue. The objective of this study is to examine incidence, trends, and factors associated with mortality in patients with osteoporotic hip fractures. METHODS: This is a retrospective cohort study that uses the Registry for Hospital Discharges of the National Health System of our hospital. Patients older than 45 having an osteoporotic hip fracture between 1999 and 2015 were identified. Demographic data and comorbidities were obtained. A survival analysis was performed (Cox regression and Kaplan-Meier). Incidence rate, standardized death rate (SDR), trend (Poisson regression), and risk (hazard ratio) were calculated. RESULTS: During 1999-2015, in our hospital, there were a total of 3992 patients admitted due to osteoporotic hip fracture. Out of these 3992 patients, 3109 patients (77.9%) were women with an average age of 84.47 years (SD 8.45) and 803 (22.1%) were men with an average age of 81.64 years (SD 10.08). The cumulative incidence of mortality was 69.38%. The cumulative mortality rate for 12 months was 33%. The annual mortality was 144.9/1000 patients/year. The 1-year mortality rate increased significantly by 2% per year (IRR 1.020, CI95% 1.008-1.033). The median overall survival was 886 days (CI95% 836-951). The probability of mortality density for a period of 10 years following a hip fracture was 16% for women and 25% for men (first 90 days). The SDR was 8.3 (CI95% 7.98-8.59). Variables that showed statistically significant association with mortality were aged over 75, masculine, institutionalization, mild to severe liver disease, chronic kidney disease, COPD, dementia, heart failure, diabetes, the Charlson Index > 2 , presence of vision disorders and hearing impairment, incontinence, and Downton scale. CONCLUSIONS: For the last 17 years, an increase of mortality for patients with hip fracture and a higher mortality rate in men than in women were observed. Institutionalization combined with comorbidities is associated with a higher mortality.

OBJECTIVE: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. RESULTS: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. CONCLUSIONS: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

Nasty/Rzany An evidence-based guideline has been defined as 'a systematically developed statement that assists clinicians and patients in making decisions about appropriate treatment for a specific condition'.1 A guideline will never encompass therapy specifications for all medical decision-making situations. Deviation from the recommendations may, therefore, be justified in specific situations. This is not a textbook on acne, nor a complete, all-inclusive reference on all aspects important to the treatment of acne. The presentation on safety in particular is limited to the information available in the included clinical trials and does not represent all the available and necessary information for the treatment of patients. Additional consultation of specific sources of information on the particular intervention prescribed (e.g. product information sheet) is necessary. Furthermore, all patients should be informed about the specific risks associated with any given topical and/or systemic therapy. Readers must carefully check the information in this guideline and determine whether the recommendations contained therein (e.g. regarding dose, dosing regimens, contraindications, or drug interactions) are complete, correct, and up-to-date. The authors and publishers can take no responsibility for dosage or treatment decisions. Improvement in the care of acne patients The idea behind this guideline is that recommendations based on a systematic review of the literature and a structured consensus process will improve the quality of acne therapy in general. Personal experiences and traded therapy concepts should be critically evaluated and replaced, if applicable, with the consented therapeutic recommendations. In particular, a correct choice of therapy should be facilitated by presenting the suitable therapy options in a therapy algorithm, taking into account the type of acne and the severity of the disease. Reduction of serious conditions and scarring As a result of the detailed description of systemic therapies for patients with severe acne, reservations about these interventions should be overcome to ensure that patients receive the optimal therapy. With the timely introduction of sufficient therapies, the development of serious post-acne conditions and severe scarring should be reduced. Promotion of adherence Good therapeutic adherence is key to treatment success. Adherence is facilitated by knowledge of the product being used, for example treatment duration, the expected onset of effect, the sequence of the healing process, the maximal achievable average effect, expected adverse events and the benefit to quality of life. Reduction of antibiotic resistance The use of topical and systemic antibiotics should be optimized by using appropriate combinations for a predefined duration, to reduce the development of antibiotic resistance. Health care professionals This guideline has been developed to help health care professionals provide optimal therapy to patients with mild, moderate or severe acne. The primary target groups are dermatologists and other professionals involved in the treatment of acne, such as paediatricians and general practitioners. The target group may vary with respect to national differences in the distribution of services provided by specialists or general practitioners. Patients The recommendations of the guideline refer to patients who suffer from acne. These are mainly adolescents treated in outpatient clinics. The appropriate therapy option is presented according to the type of acne that is present. The primary focus is the induction therapy of facial acne (see Chapter 1.6). Non-primary target groups are patients with special forms of acne, such as, occupational acne, chloracne, acne aestivalis, acne neonatorum, acne inverse (hidradenitis suppurativa). European guidelines are intended for adaptation to national conditions. It is beyond the scope of this guideline to take into consideration the specific costs and reimbursement situations in every European country. Differences in prices, reimbursement systems, willingness and ability to pay for medication among patients and the availability of generics are too large. Therefore, pharmacoeconomic considerations will have to be taken into account when guidelines are developed at national and local levels. The personal financial and health insurance situation of a patient may necessitate amendments to the prioritization of treatment recommendations. However, if financial resources allow, the suggested ranking in the therapeutic algorithm should be pursued. The skin type and stage of disease has to be taken into consideration when choosing the vehicle for topical treatments. The efficacy and safety/tolerability of topical treatments are largely influenced by the choice of vehicle. The face is the primary region of interest for the treatment of acne. Appearance, scarring, quality of life and social stigmatization are important considerations when dealing with facial dermatological diseases. The recommendations of this guideline apply primarily to the treatment of facial acne. More widespread involvement will certainly favour earlier use of a systemic treatment due to the efficacy and practicability of such treatments. Layton/Finlay Acne (synonym 'acne vulgaris') is a polymorphic, inflammatory skin disease most commonly affecting the face (99% of cases). Less frequently it also affects the back (60%) and chest (15%).2 Seborrhoea is a frequent feature.3 The clinical picture embraces a spectrum of signs, ranging from mild comedonal acne, with or without sparse inflammatory lesions (IL), to aggressive fulminate disease with deep-seated inflammation, nodules and in some cases associated systemic symptoms. Clinically non-inflamed lesions develop from the subclinical microcomedo which is evident on histological examination early in acne development.2 Non-inflamed lesions encompass both open (blackheads) and closed comedones (whiteheads). Comedones frequently have a mid-facial distribution in childhood and, when evident early in the course of the disease, this pattern is indicative of poor prognosis.4 Closed comedones are often inconspicuous with no visible follicular opening. Most patients have a mixture of non-inflammatory (NIL) and inflammatory lesions.5 Inflammatory lesions arise from the microcomedo or from non-inflammatory clinically apparent lesions and may be either superficial or deep.6 Superficial inflammatory lesions include papules and pustules (5 mm or less in diameter). These may evolve into deep pustules or nodules in more severe disease. Inflammatory macules represent regressing lesions that may persist for many weeks and contribute markedly to the general inflammatory appearance.5 Small nodules are defined as firm, inflamed lesions >5 mm diameter, painful by palpation. Nodules are defined as larger than 5 mm, large nodules are >1 cm in size. They may extend deeply and over large areas, frequently resulting in painful lesions, exudative sinus tracts and tissue destruction. Conglobate acne is a rare but severe form of acne found most commonly in adult males with few or no systemic symptoms. Lesions usually occur on the trunk and upper limbs and frequently extend to the buttocks. In contrast to ordinary acne, facial lesions are less common. The condition often presents in the second to third decade of life and may persist into the sixth decade. Conglobate acne is characterized by multiple grouped comedones amidst inflammatory papules, tender, suppurative nodules which commonly coalesce to form sinus tracts. Extensive and disfiguring scarring is frequently a feature. There are several severe and unusual variants or complications of acne as well as other similar diseases. These include acne fulminans, gram-negative folliculitis, rosacea fulminans, vasculitis, mechanical acne, oil/tar acne, chloracne, acne in neonates and infants and late onset, persistent acne, sometimes associated with genetic or iatrogenic endocrinopathies. The current guidelines do not lend themselves to comprehensive management of all these variants. Finlay/Layton Acne can be largely assessed from two perspectives: objective disease activity (based on measurement of visible signs) and quality of life impact. There are other aspects of measurement, such as sebum excretion rate, scarring development or economic impact. There are inherent difficulties in objectively measuring acne. Over 25 different methods have been described7 but there is no consensus as to which should be used. Most methods are non-validated and consequently the results of separate trials cannot be directly compared. There are detailed reviews on this subject by Barratt et al.,8 Witkowski et al.,9 Thiboutot et al.,10 and Gollnick et al.11 Proper lighting, appropriate patient positioning and prior facial skin preparation (gentle shaving for men, removal of make-up for women) are helpful in facilitating accurate assessment. Palpation in addition to visual inspection may also help define lesions more accurately. Many methods for measuring acne have been described, ranging from global assessments to lesion counting.7, 9 Despite a range of methods being used to measure acne in the 1960's and 1970's, it was the Leeds technique12 that dominated acne measurement for the next two decades. The Leeds technique included two methods; the grading technique and the counting technique. The grading technique allocated patients a grade from 0 to 10, with seven subgroups between 0 and 2. Photographic guides illustrating each grade are given, but the importance of palpating lesions is also stressed. The experience on which this system was based stemmed from the pre-isotretinoin era, and acne of the severity described by grades above 2 is now rarely seen. The counting technique involves the direct counting of non-inflamed and inflamed lesions, including superficial papules and pustules, deep inflamed lesions and macules. The revised Leeds acne grading system13 includes numerical grading systems for the back and chest as well as for the face. The Echelle de Cotation des Lesions d'Acne (ECLA) or 'Acne Lesion Score Scale' system has demonstrated good reliability.14 However, ECLA scores do not correlate with quality of life scores and the use of both disease and quality of life scores is suggested.15 Global assessment scales incorporate the entirety of the clinical presentation into a single category of severity. Each category is defined by either a photographic repertoire with corresponding numeric scale or descriptive text. Grading is a subjective task, based on observing dominant lesions, evaluating the presence or absence of inflammation, which is particularly difficult to capture, and estimating the extent of involvement. Global methods are much more practically suited to clinical practice. In clinical investigations, they should be combined with lesion counts as a co-primary endpoint of efficacy.16 A simple photographic standard-based grading method using a 0–8 scale has been successfully employed in a number of clinical trials.17 In 2005, the US FDA proposed an IGA (investigator global assessment) that represented a static quantitative evaluation of overall acne severity. To accomplish this, they devised an ordinal scale with five severity grades, each defined by distinct and clinically relevant morphological descriptions that they hoped would minimize inter-observer variability. Indeed, the more detailed descriptive text has resulted in this system being considered to provide even greater reliability than previous global assessments.16 A very simple classification of acne severity was described in the 2003 report from the Global Alliance for better outcome of acne treatment.11 This basic classification was designed to be used in a routine clinic, and its purpose was to map treatment advice onto common clinical presentations. For each acne descriptor a first-choice therapy is advised, with alternatives for female patients and maintenance therapy. There are five simple descriptors: mild comedonal, mild papulopustular, moderate papulopustular, moderate nodular and severe nodular/conglobate. A series of eight photographs span and overlap these five descriptors. Different facial views and different magnifications are used, reducing the comparability of the images. To give treatment recommendations based on disease activity, the EU Guidelines group has considered how best to classify acne patients. It has used the following simple clinical classification: Comedonal acne Mild–moderate papulopustular acne Severe papulopustular acne, moderate nodular acne Severe nodular acne, conglobate acne Other already existing systems are very difficult to compare with one another. The group has tried to map the existing systems to the guidelines' clinical classification. However, in many cases the systems do not include corresponding categories and often it has to be considered an approximated narrowing rather than a precise mapping (Table 1). Simpson and Cunliffe25'consider the use of quality of life and psychosocial questionnaires essential to adequately understanding just how the disease is affecting the patient, and to better understand the progress of the disease'. The impact of acne on quality of life can be measured using general health measures, dermatology-specific measures or acne-specific measures. In order for quality of life measures to be used more frequently in the routine clinical work, they need to be easy to use, the scores need to be meaningful and they need to be readily accessible. Clinicians must be convinced that the information gained from using them is of benefit in guiding them to make optimum clinical decisions for their patients, and they need to become aware that the use of these measures may help to justify their clinical decisions. Quality of life measures can influence the choice of therapy. In patients with a severe impact on their quality of life, a more aggressive therapy may be justified. A number of prognostic factors relating to more severe disease should be considered when assessing and managing acne. These are outlined and evidenced in review papers published by Holland and Jeremy 200526 and Dreno et al. 200827 and include family history, course of inflammation, persistent or late-onset disease, hyperseborrhoea, androgenic triggers, truncal acne and/or psychological sequelae. Previous infantile acne may also correlate with resurgence of acne at puberty and early age of onset with mid-facial comedones, early and more severe seborrhoea and earlier presentation relative to menarche are all factors that should alert the clinician to increased likelihood of more severe acne. Scarring usually follows deep-seated inflammatory lesions, but may also occur as a result of more superficial inflamed lesions in scar-prone patients. Acne scarring, albeit mild, has been identified in up to 90% of patients attending a dermatology clinic.28 Scars may show increased collagen (hypertrophic and keloid scars) or be associated with collagen loss. The presence of scarring should support aggressive management and therapy should be commenced early in the disease process. (For further details please see the methods report at http://www.acne-guidelines.com.) Nast/Rzany All experts were officially nominated by the European Dermatology Forum (EDF) or the European Academy of Dermatology and Venereology. They were selected according to their clinical expertise, publication record and/or experience in the field of evidence-based medicine and guideline development. None of the experts received any financial incentive other than reimbursement of travel costs. Participation of patients was difficult to realize, since no patient organization exists. Attempts to invite patients currently treated by the involved experts did not succeed. Patients were invited to participate in the external review. Patient preference was considered as an important outcome and trials looking at patient preferences were included. There is a vast array of treatment options available for acne. The options are further extended by the availability of different vehicles and formulations. When choosing a treatment, different skin types, ethnic groups and subtypes of acne must also be considered. The authors of this guideline selected the most relevant treatments in Europe to be included in the guideline. The fact that a certain treatment was not selected as a topic for this guideline, does not mean that it may not be a good treatment for acne. Additional treatment options may be considered for a later update. Fixed-dose combinations were considered as long as they were licensed in a European country (e.g. adapalene + benzoyl peroxide (BPO), clindamycin + BPO, erythromycin + tretinoin, erythromycin + isotretinoin, erythromycin + zinc). Treatment options consisting of more than two topical components were not included because of the likeliness of reduced patient adherence and/or because of a limitation in the feasibility of discussing all possible combinations and sequences. An extensive search of existing guidelines and systematic reviews was performed at the beginning of the project. The search was performed in Medline, Embase, and Cochrane (for search strategies see the methods report at http://www.acne-guidelines.com). The date of the systematic searches was March 10th 2010 for topical and systemic interventions and April 13th 2010 for laser and light therapies. The results were checked for the inclusion criteria and trial quality using a standardized literature evaluation form. Existing systematic reviews (e.g. Cochrane) and other guidelines served as an additional basis for the body of evidence in this guideline. Pooling of the trials was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data (for details of search strategies, standardized evaluation form and references of included reviews see methods report at http://www.acne-guidelines.com). The aim of this guideline is to give recommendations for specific clinical conditions, e.g. the severity of acne, and not to assess the different medications one by one without respect to clinical stage. However, most trials did not look in detail at subtypes but include patients with 'acne vulgaris' in general. Therefore, for some recommendations, 'indirect evidence' was generated from looking at suitable outcome parameters: The percentage 'reduction of non-inflammatory lesions' was the efficacy parameter considered for comedonal acne. Efficacy in papulopustular acne was assessed by 'reduction in inflammatory lesions', 'reduction in total lesion count' and other acne grading scales. The generation of evidence for nodular/conglobate acne was particularly difficult, since very few trials included nodular/conglobate acne. Consequently, treatment recommendations also took into account indirect data from trials of severe papulopustular acne. The evidence from clinical trials almost always focuses on facial acne. Trials that examined acne at other locations (e.g. back), were considered as indirect evidence and the level of evidence was downgraded accordingly. Very little attention has been given during clinical trials to the question of a minimal clinically important difference from the perspective of the patient. It would be helpful to know the extent of reduction in the number of acne lesions required for patients to consider that there has been a clinically important improvement. One study has been identified that empirically validated a non-inferiority margin of 10–15% for facial acne lesion counts as appropriate.356 The consensus view of the authors of this guideline is that a treatment should achieve at least a 10% greater reduction in the number of lesions to demonstrate superior efficacy. for the evaluation of superior or efficacy the evidence generation process, a 10% difference in efficacy was considered Many different grading systems for assessing the quality of evidence are available in the field of guideline development. For this guideline, the authors used the grading system for the European Guidelines with some taken from the The available literature was evaluated with respect to the quality of each single A grade of evidence was given to every trial clinical trial of quality of patient sufficient clinical trial of quality (e.g. limited at least patients trial with severe (e.g. not very no When looking at a specific question (e.g. efficacy of relative to the available evidence was by a level of evidence using the following is very to in the of least two trials are available that were a grade of evidence A and the results are with the results of additional grade or is to have an important impact on in the of and may the least trials are available that were a grade of evidence and the results are with respect to additional grade is very to have an important impact on in the of and is to the evidence or limited of with a grade of evidence of or of is very or no systematic included trials are limited in number and/or All recommendations were in a consensus of the authors using consensus group The consensus was by who is a for the of All of the were to in the consensus In a consensus was In the absence of a this was in the text and for the difference in views were All consensus are in a the text. To the different recommendations, the group a of grade (see The of considered all aspects of the treatment such as patient preference and the reliability of the existing body of evidence of of To grade the a guidelines' was be be considered. not not be used any A for or treatment cannot be at the An extensive external review was dermatological Dermatology Forum (EDF) other general as in the European of and patients were invited to was open and it was possible for to the the The group the guidelines their and performed a trial their clinics. (For further details see the methods report at will be at a national level by local medical such as an a and a therapeutic algorithm will be for evaluation (e.g. assessment of treatment and patient are in preparation and will be at a national Guidelines need to be to the of medical information This guideline will not be In of important in the licensed of drug important an will be The guidelines the of the of evidence-based medicine will the for an by of a Acne is one of the most frequent skin diseases. in the of acne in adolescents to be between and on the method of lesion mild were and moderate or severe were the was Acne is a disease primarily of It is in by the of by the and and it usually the of However, to some acne may persist beyond in a of particularly the disease has acne and are not factors have been there is a among and there is also a severe acne in patients with a family for little is about specific It is that several are involved in an to acne. These include the for and and ethnic factors may also contribute to differences in the clinical presentation and of factors also to be of to the of with a not to develop In particular, has gained with and a between acne and Acne is an of There are primary which to acne sebum by the in the process, follicular and of inflammatory Patients with seborrhoea and acne have a greater number of with Inflammatory occur prior to the of to the development of comedones of the with A relative has also been are by which in with to and as well as the in by and are also involved in activity as are the such as and The also as an in to in and other can of and a Acne factors and the of and induction by 2 of and of the of which and the The understanding of acne development on a level that acne is a disease that involves both and systems and inflammatory are based on available evidence and evidence and to classification of of (Table one trial at patients with comedonal acne. As a of indirect trials including patients with papulopustular acne were used and the percentage in the reduction of non-inflammatory lesions was considered as the relevant outcome of the general lack of direct evidence for the treatment of comedonal acne, the of was downgraded for all considered treatment with of as a of topical systemic treatment to the usually severity of comedonal acne, a topical therapy is efficacy was defined as a difference of in the reduction of non-inflammatory lesions in (see also Chapter efficacy with is demonstrated and the topical (Table the topical

Cannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB(1) cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB(1) receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB(1) receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB(2) cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB(2) receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB(2) receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB(2) receptor-mediated actions. These findings support a pivotal role for CB(2) receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.

This is a short summary of the complete version of the S3 European Acne guideline, please see online appendix for full text (Document S1. Long Version) and detailed methods report (DOI: 10.1111/jdv.13783). Expiry date: 31 December 2020 In order to grade the recommendation a “standardized guideline” language was used: Recommendations are based on available evidence and expert consensus. Available evidence and expert voting lead to classification of strength of recommendation. Adapalene + BPO (f.c.) or BPO + Clindamycin (f.c.) e Azelaic acid or BPO or Topical Retinoid d or Topical Clindamycin + Tretinoin (f.c.) e,f or Systemic Antibiotic e,g,h + Adapalene i Systemic Antibiotic e,h + Adapalene i or Systemic Antibiotic e,h + Azelaic acid j or Systemic Antibiotic e,h + Adapalene + BPO (f.c.) Systemic Antibiotic e,h + Azelaic Acid or Systemic Antibiotic e,h + Adapalene + BPO (f.c.) Azelaic acid or BPO Blue Light or Oral Zinc or Systemic Antibiotic e,g,h + Azelaic Acid j or Systemic Antibiotic e,g,h + Adapalene + BPO (f.c.) k or Systemic Antibiotic e,g,h + BPO l or Topical Erythromycin + Isotretinoin (f.c.) e or Topical Erythromycin + Tretinoin (f.c.) e Systemic Antibiotic e,h + Adapalene i,k or Systemic Antibiotics e,h + BPO k Hormonal Anti-androgens + Systemic Antibiotic e,h + Topicals (apart from antibiotics) or Hormonal Anti-androgens + Topical Treatment (apart from antibiotics) Hormonal Anti-androgens + Systemic Antibiotic e,h + Topicals (apart from antibiotics) or Hormonal Anti-androgens + Topical Treatment (apart from antibiotics) Recommendations for comedonal acne a High strength of recommendation None Medium strength of recommendation Topical retinoids b can be recommended for the treatment of comedonal acne. Low strength of recommendation Azelaic acid can be considered for the treatment of comedonal acne. BPO can be considered for the treatment of comedonal acne. Open recommendation A recommendation for or against treatment of comedonal acne with visible light as monotherapy, lasers with visible wavelengths and lasers with infrared wavelengths, with intense pulsed light (IPL) and photodynamic therapy (PDT) cannot be made at the present time. Negative recommendation Topical antibiotics are not recommended for the treatment of comedonal acne. Hormonal anti-androgens, systemic antibiotics and/or systemic isotretinoin are not recommended for the treatment of comedonal acne. Artificial ultraviolet (UV) radiation is not recommended for the treatment of comedonal acne. Only one trial looks specifically at patients with comedonal acne. As a source of indirect evidence, trials including patients with papulopustular acne were used and the percentage in the reduction of non-inflammatory lesions was considered as the relevant outcome parameter. Because of the general lack of direct evidence for the treatment of comedonal acne, the strength of recommendation was downgraded for all considered treatment options, starting with medium strength of recommendation as a maximum. Due to the usually mild to moderate severity of comedonal acne, generally, a topical therapy is recommended. The best efficacy was shown for topical retinoids, BPO and azelaic acid. The tolerability of topical retinoids and BPO is comparable; there is a trend towards azelaic acid having a better safety/tolerability profile than BPO and a comparable profile to adapalene (indirect evidence, see Table 11 in long version). The fixed-dose combination of adapalene with BPO shows a trend towards better efficacy against non-inflammatory lesions (NIL) when compared to BPO and a comparable efficacy when compared to adapalene (see Table 4 in long version). However, there is also a trend towards inferiority of the fixed combination with respect to the safety/tolerability profile (indirect evidence, see Table 12 in long version). The fixed-dose combinations of clindamycin with BPO showed a trend towards better efficacy against NIL vs. clindamycin and comparable efficacy vs. BPO (see Table 5 in long version). With respect to the safety/tolerability profile, the combination is comparable to its single components (indirect evidence, see Table 12 in long version). Few and only indirect data on patient preference are available. They indicate patient preference for adapalene over other topical retinoids. Additional pathophysiological considerations favour the use of topical retinoids (reduction of microcomedones). Recommendations for mild to moderate papulopustular acne a High strength of recommendation The fixed-dose combination adapalene and BPO is strongly recommended for the treatment of mild to moderate papulopustular acne. The fixed-dose combination BPO and clindamycin b is strongly recommended for the treatment of mild to moderate papulopustular acne. Medium strength of recommendation Azelaic acid can be recommended for the treatment of mild to moderate papulopustular acne. BPO can be recommended for the treatment of mild to moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with adapalene g can be recommended for the treatment of moderate papulopustular acne. f The fixed-dose combination clindamycin and tretinoin b can be recommended for the treatment of mild to moderate papulopustular acne. Topical retinoids g can be recommended for the treatment of mild to moderate papulopustular acne. Low strength of recommendation Blue light monotherapy can be considered for the treatment of mild to moderate papulopustular acne. Oral zinc can be considered for the treatment of mild to moderate papulopustular acne. Systemic antibiotic b,c,d in combination with azelaic acid h can be considered for the treatment of mild to moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with adapalene in fixed-dose combination with BPO i can be considered for the treatment of moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with BPO j can be considered for the treatment of moderate papulopustular acne. The fixed-dose combination of erythromycin and isotretinoin b can be considered for the treatment of mild to moderate papulopustular acne. The fixed-dose combination of erythromycin and tretinoin b can be considered for the treatment of mild to moderate papulopustular acne. Open recommendation Due to a lack of sufficient evidence, a recommendation for or against treatment of mild to moderate papulopustular acne with red light, IPL, Laser or PDT cannot be made at the present time. Negative recommendation Topical antibiotics as monotherapy are not recommended for the treatment of mild to moderate papulopustular acne. Artificial UV radiation is not recommended for the treatment of mild to moderate papulopustular acne. The fixed-dose combination of erythromycin and zinc is not recommended for the treatment of mild to moderate papulopustular acne. Systemic therapy with anti-androgens, antibiotics, and/or isotretinoin is not recommended for the treatment of mild to moderate papulopustular acne. Recommendations for severe papulopustular/moderate nodular acne a High strength of recommendation Oral isotretinoin monotherapy is strongly recommended for the treatment of severe papulopustular/moderate nodular acne. Medium strength of recommendation Systemic antibiotics b,c in combination with adapalene d, with the fixed-dose combination of adapalene and BPO, or in combination with azelaic acid e can be recommended for the treatment of severe papulopustular/moderate nodular acne. Low strength of recommendation Systemic antibiotics b,c in combination with BPO e can be considered for the treatment of severe papulopustular/moderate nodular acne. For females: Hormonal anti-androgens in combination with systemic antibiotic b,c and topicals (apart from antibiotics) can be considered for the treatment of severe papulopustular/moderate nodular acne. For females: Hormonal anti-androgens in combination with a topical treatment (apart from antibiotics) can be considered for the treatment of severe papulopustular/moderate nodular acne. Open recommendation Due to a lack of sufficient evidence, a recommendation for or against treatment of severe papulopustular/moderate nodular acne with red light, IPL, laser or PDT cannot be made at the present time. Although PDT is effective in the treatment of severe papulopustular/moderate nodular acne, a recommendation for or against its use cannot be made at the present time due to a lack of standard treatment regimens that ensure a favourable profile of acute adverse reaction. Negative recommendation Single or combined topical monotherapy is not recommended for the treatment of severe papulopustular/moderate nodular acne. Oral antibiotics as monotherapy are not recommended for the treatment of severe papulopustular/moderate nodular acne. Oral anti-androgens as monotherapy are not recommended for the treatment of severe papulopustular/moderate nodular acne. Visible light as monotherapy is not recommended for the treatment of severe papulopustular/moderate nodular acne. Artificial UV radiation sources are not recommended as a treatment of severe papulopustular/moderate nodular acne. Monotherapy with azelaic acid, BPO or topical retinoids showed superior efficacy when compared with vehicle. Adapalene, azelaic acid and BPO showed comparable efficacy when compared with each other. When comparing the topical retinoids (adapalene, isotretinoin and tretinoin) directly against each other, no relevant difference with respect to efficacy was seen. Some conflicting evidence to the comparability of the efficacy of the treatment options above arises, when looking at the other head to head comparisons indicating superiority of BPO over isotretinoin and tretinoin over azelaic acid. With respect to the fixed combinations, BPO/clindamycin shows superiority over both single components. The three fixed combinations of adapalene/BPO, clindamycin/tretinoin as well as erythromycin/isotretinoin show superiority to one of the components but not to both of the components when compared individually. Head to head comparisons of the fixed combinations of adapalene/BPO vs. BPO/clindamycin as well as head to head comparisons of clindamycin/tretinoin vs. BPO/clindamycin show comparable efficacy. Due to the serious concerns regarding the risk of developing antibiotic resistance, topical monotherapy with antibiotics is generally not recommended. The potential risk of developing antibiotic resistance was taken into consideration by the expert group. It led to a medium strength of recommendation for the fixed combination of clindamycin/tretinoin despite comparable efficacy and safety when compared to the fixed combination of BPO/clindamycin. The differentiation between clindamycin/tretinoin (medium strength of recommendation) and erythromycin/isotretinoin (low strength of recommendation) was based on evidence showing the lack of development of antibiotic resistance after 16 weeks of treatment with clindamycin/tretinoin as well as indirect evidence on stronger development of antibiotic resistance to erythromycin and expert opinion on better follicular penetration and galenic of the clindamycin/tretinoin f.c. formulation. Monotherapy with azelaic acid, BPO or topical retinoids showed comparable efficacy when compared with each other. For severe cases, systemic treatment with isotretinoin is recommended based on the very good efficacy seen in clinical practice. The available evidence on safety and tolerability is extremely scarce and was considered insufficient to be used as a primary basis to formulate treatment recommendations. The lack of standardized protocols, experience and clinical trial data mean there is insufficient evidence to recommend the treatment of papulopustular acne with laser and light sources other than blue light. There are limited data comparing topical treatments with a systemic treatment or the additional effect of a combination of a topical plus systemic vs. topical treatment only. Most of the available trials compare a topical antibiotic monotherapy with a systemic antibiotic monotherapy. Issues of practicability between topical and systemic treatments must also be taken into consideration in cases of severe, and often widespread, disease. The consensus within the expert group was that most cases of severe papulopustular acne or moderate nodular acne, will achieve better efficacy when a systemic antibiotic treatment in combination with a topical treatment or if systemic isotretinoin is used. Involvement of the trunk areas plays an important role. In addition, better adherence and patient satisfaction is anticipated for systemic treatments. Recommendations for severe nodular/conglobate acne a High strength of recommendation Oral isotretinoin is strongly recommended as a monotherapy for the treatment of severe nodular/conglobate acne. Medium strength of recommendation Systemic antibiotics b,c in combination with the fixed-dose combination of adapalene and BPO or in combination with azelaic acid can be recommended for the treatment of severe nodular/conglobate acne. Low strength of recommendation Systemic antibiotics b,c in combination with adapalene d,e or BPO e can be considered for the treatment of severe nodular/conglobate acne. For females: Hormonal anti-androgens in combination with systemic antibiotic b,c and topicals (apart from antibiotics) can be considered for the treatment of severe nodular/conglobate acne. For females: Hormonal anti-androgens in combination with a topical treatment can be considered for the treatment of severe nodular/conglobate acne. Open recommendation Due to a lack of sufficient evidence, it is currently not possible to make a recommendation for or against treatment with IPL or laser in severe nodular/conglobate acne. Although PDT is effective in the treatment of severe nodular/conglobate acne, it cannot yet be recommended due to a lack of standard treatment regimens that ensure a favourable profile of acute adverse reaction. Negative recommendation Topical monotherapy is not recommended for the treatment of conglobate acne. Oral antibiotics are not recommended as monotherapy for the treatment of severe nodular/conglobate acne. Oral anti-androgens are not recommended as monotherapy for the treatment of severe nodular/conglobate acne. Artificial UV radiation sources are not recommended for the treatment of severe nodular/conglobate acne. Visible light as monotherapy is not recommended for the treatment of severe nodular/conglobate acne. Very few of the included trials (see long version) looked specifically at patients with nodular or conglobate acne. As a source of indirect evidence, studies of patients with severe papulopustular acne were used and the percentage in the reduction of nodules (NO) and cysts (CY) in these studies was used. In case of use of such indirect evidence, the strength of recommendation was downgraded for the considered treatment options. Systemic isotretinoin shows superior efficacy in the treatment of severe nodular/conglobate acne when compared with systemic antibiotics or topical therapy only. The expert group considered that the greatest effectiveness in the treatment of severe nodular/conglobate acne in clinical practice is seen with systemic isotretinoin. This can only be partly supported by published evidence, due to the scarcity of clinical trials in conglobate acne. In the experts’ opinion, safety concerns with isotretinoin are manageable if treatment is properly initiated and monitored. Patient benefit with respect to treatment effect, improvement in quality of life and avoidance of scarring outweigh the side-effects. Adapalene should be selected in preference to tretinoin and isotretinoin. Doxycycline and lymecycline should be selected in preference to minocycline and tetracycline. For severe papulopustular acne/moderate nodular acne, a dosage of systemic isotretinoin of 0.3–0.5 mg/kg can be recommended. For conglobate acne a dosage of systemic isotretinoin of ≥0.5 mg/kg canbe recommended. The duration of the therapy should be at least 6 months. In case of insufficient response, the treatment period can be prolonged. Azelaic Acid or Topical Retinoid b Azelaic Acid or BPO or Topical Retinoid b Adapalene + BPO (f.c.) c or Azelaic Acid or BPO c or Low Dose Systemic Isotretinoin (max. 0.3 mg/kg/day) or Topical Retinoid b Adapalene + BPO (f.c.) c or Azelaic Acid or BPO c or Low Dose Systemic Isotretinoin (max. 0.3 mg/kg/day) or Topical Retinoid b A maintenance treatment, especially for the patients with “particular need for a maintenance treatment” as defined below, is recommended. The low strength of recommendation provided below reflects primarily the lack of good evidence as to which is the best treatment and does not put into question the need for maintenance therapy in general. Available evidence indicates efficacy of azelaic acid, topical retinoids and adapalene/BPO over vehicle during maintenance treatment. Pathophysiological data supports use of azelaic acid, topical retinoids and adapalene based on their demonstrated efficacy on microcomedones. Any use of topical or systemic antibiotics is not recommended on a long-term base/during maintenance therapy. The development of guidelines is a time and resource intensive process and currently no public funding is available for European guidelines. In order to be able to produce high quality guidelines, the EDF uses its membership contributions and asks its cooperative partners for support (see Funding source). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Two types of cannabinoid receptors have been characterized so far, CB1 and CB2. While CB1 receptors are present both in the CNS and in the periphery, CB2 receptors showed an almost exclusive distribution within the immune system. We now report that CB2 receptors are present in a specific microglial cell type of the human cerebellum. Thus, we have performed immunohistochemical analysis of tissue sections of white matter areas of the human cerebellum and detected the presence of CB2 receptors in perivascular microglial cells. These findings match with the well-known immunomodulatory role of CB2 receptors and open new perspectives on the possible role that these receptors may play in pathophysiological events.

BACKGROUND: The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohn's disease (CD), in a large, long-term, follow-up study. METHODS: The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow-up was 12 months in patients showing no relapse and until activity flare in relapsing patients. RESULTS: In all, 163 patients (89 CD, 74 UC) were included. Twenty-six patients (16%) relapsed during follow-up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 +/- 150 versus 136 +/- 158 microg/g; P < 0.001). Relapse risk was higher in patients having high (>150 microg/g) calprotectin concentrations (30% versus 7.8%; P < 0.001) or positive lactoferrin (25% versus 10%; P < 0.05). Fecal calprotectin (>150 microg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan-Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis. CONCLUSIONS: Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse-especially during the following 3 months-in both CD and UC patients.

BACKGROUND: Major surgery is frequently associated with postoperative cognitive dysfunction (POCD) in elderly patients. Type of surgery and hospitalization may be important prognostic factors. The aims of the study were to find the incidence and risk factors for POCD in elderly patients undergoing minor surgery. METHODS: We enrolled 372 patients aged greater than 60 years scheduled for minor surgery under general anesthesia. According to local practice, patients were allocated to either in- (199) or out-patient (173) care. Cognitive function was assessed using neuropsychological testing preoperatively and 7 days and 3 months postoperatively. Postoperative cognitive dysfunction was defined using Z-score analysis. RESULTS: At 7 days, the incidence (confidence interval) of POCD in patients undergoing minor surgery was 6.8% (4.3-10.1). At 3 months the incidence of POCD was 6.6% (4.1-10.0). Logistic regression analysis identified the following significant risk factors: age greater than 70 years (odds ratio [OR]: 3.8 [1.7-8.7], P = 0.01) and in- vs. out-patient surgery (OR: 2.8 [1.2-6.3], P = 0.04). CONCLUSIONS: Our finding of less cognitive dysfunction in the first postoperative week in elderly patients undergoing minor surgery on an out-patient basis supports a strategy of avoiding hospitalization of older patients when possible.

Thirty-five patients aged 14-74 years (average, 54 years) who had brucellar spondylitis were treated between January 1991 and December 1997. The time from onset of symptoms to diagnosis of spondylitis ranged from 1 week to 8 months (median, 9 weeks). Back or neck pain (100% of patients), fever (66%), and constitutional symptoms (57%) were the most common symptoms. Cultures of blood specimens from 26 patients (74%) were positive for Brucella melitensis. The duration of antimicrobial therapy (median, 120 days; range, 45-535 days) varied according to clinical response and the presence of epidural and paravertebral masses. One of the 35 patients underwent surgical treatment of a spinal epidural abscess. Therapy failed for 9 patients (26%; 95% confidence interval [CI], 12%-43%), and 5 (14%; 95% CI, 5%-30%) had a relapse. There were no deaths or severe sequelae in this study. Brucellar spondylitis causes considerable suffering and absenteeism from work, but long-term clinical responses are favorable.

The presence of functional cannabinoid CB2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amounts and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB1, makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB1 activation have largely limited the clinical use of cannabinoid-related compounds that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addition, various working hypotheses are also proposed and discussed.

Present pain models for tension-type headache suggest that nociceptive inputs from peripheral tender muscles can lead to central sensitization and chronic tension-type headache (CTTH) conditions. Such models support that possible peripheral mechanisms leading to pericranial tenderness include activation or sensitization of nociceptive nerve endings by liberation of chemical mediators (bradikinin, serotonin, substance P). However, a study has found that non-specific tender points in CTTH subjects were not responsible for liberation of algogenic substances in the periphery. Assuming that liberation of algogenic substances is important, the question arising is: if tender muscle points are not the primary sites of on-going neurogenic inflammation, which structure can be responsible for liberation of chemical mediators in the periphery? A recent study has found higher levels of algogenic substances, and lower pH levels, in active myofascial trigger point (TrPs) compared with control tender points. Clinical studies have demonstrated that referred pain elicited by head and neck muscles contribute to head pain patterns in CTTH. Based on available data, an updated pain model for CTTH is proposed in which headache can at least partly be explained by referred pain from TrPs in the posterior cervical, head and shoulder muscles. In this updated pain model, TrPs would be the primary hyperalgesic zones responsible for the development of central sensitization in CTTH.

This paper describes the differences in the presence of myofascial trigger points (TrPs) in the upper trapezius, sternocleidomastoid, temporalis and suboccipital muscles between unilateral migraine subjects and healthy controls, and the differences in the presence of TrPs between the symptomatic side and the non-symptomatic side in migraine subjects. In addition, we assess the differences in the presence of both forward head posture (FHP) and active neck mobility between migraine subjects and healthy controls and the relationship between FHP and neck mobility. Twenty subjects with unilateral migraine without side-shift and 20 matched controls participated. TrPs were identified when there was a hypersensible tender spot in a palpable taut band, local twitch response elicited by the snapping palpation of the taut band and reproduction of the referred pain typical of each TrP. Side-view pictures were taken in both sitting and standing positions to measure the cranio-vertebral angle. A cervical goniometer was employed to measure neck mobility. Migraine subjects showed a significantly greater number of active TrPs (P<0.001), but not latent TrPs, than healthy controls. Active TrPs were mostly located ipsilateral to migraine headaches (P<0.01). Migraine subjects showed a smaller cranio-vertebral angle than controls (P<0.001), thus presenting a greater FHP. Neck mobility in migraine subjects was less than in controls only for extension (P=0.02) and the total range of motion in flexion/extension (P=0.01). However, there was a positive correlation between the cranio-vertebral angle and neck mobility. Nociceptive inputs from TrPs in head and neck muscles may produce continuous afferent bombardment of the trigeminal nerve nucleus caudalis and, thence, activation of the trigeminovascular system. Active TrPs located ipsilateral to migraine headaches might be a contributing factor in the initiation or perpetuation of migraine.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated in type 2 diabetes and obesity for their high efficacy in controlling glycaemia and inducing body weight loss, respectively. Patients may develop gastrointestinal adverse events (GI AEs), namely nausea, vomiting, diarrhoea and/or constipation. To minimize their severity and duration, healthcare providers (HCPs) and patients must be aware of appropriate measures to follow while undergoing treatment. An expert panel comprising endocrinologists, nephrologists, primary care physicians, cardiologists, internists and diabetes nurse educators convened across virtual meetings to reach a consensus regarding these compelling recommendations. Firstly, specific guidelines are provided about how to reach the maintenance dose and how to proceed if GI AEs develop during dose-escalation. Secondly, specific directions are set about how to avoid/minimize nausea, vomiting, diarrhoea and constipation symptoms. Clinical scenarios representing common situations in daily practice, and infographics useful to guide both HCPs and patients, are included. These recommendations may prevent people with T2D and/or obesity from withdrawing from GLP-1 RAs treatment, thus benefitting from their superior effect on glycaemic control and weight loss.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB1 and CB2 receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB1 receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB1 receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-alpha, respectively. CB1 receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB2 receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB2-positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB1 and CB2 receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

BACKGROUND: Impulse control disorders (ICDs) encompass a wide spectrum of abnormal behaviour frequently found in cases of Parkinson's disease (PD) treated with dopamine agonists (DAs). The main aim of this study was to analyse ICD prevalence with different DAs. METHODS: We carried out a multicentre transversal study to evaluate the presence of ICDs in patients with PD chronically treated (>6 months) with a single non-ergolinic DA (pramipexole, ropinirole, or rotigotine). Clinical assessment of ICD was performed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease. RESULTS: Thirty-nine per cent of patients (91/233) fulfilled the clinical criteria for ICD. The group of patients with ICD symptoms (ICD+) differed from those without ICD symptoms (ICD-) in younger age and type of DA intake. Oral DA treatment (pramipexole and ropinirole) was associated with higher risk of ICDs compared with transdermal DA (rotigotine): 84/197 (42%) patients treated with oral DA developed ICD, versus 7/36 (19%) patients treated with transdermal DA (Fisher's exact text <0.01). In univariate analysis, a younger age (p<0.01), treatment with rasagiline (p<0.05), and especially treatment with an oral DA (pramipexole or ropinirole) (p<0.01) were significantly associated with ICD. Multivariate analysis confirmed that oral DA remained significantly associated with ICD (p: 0.014, OR: 3.14; 1.26-7.83). CONCLUSIONS: ICD was significantly associated with the use of the non-ergolinic oral DA (pramipexole and ropinirole) when compared with transdermal non-ergolinic DA (rotigotine). Since pramipexole, ropinirole and rotigotine are non-ergolinic DAs with very similar pharmacodynamic profiles, it is likely that other factors including route of administration (transdermal vs oral) explain the difference in risk of ICD development.

BACKGROUND: Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality. METHODS: In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy. RESULTS: Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60-79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17-10.1 vs < 50 years), > 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20). CONCLUSIONS: In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.