Enhancing educational and vocational recovery in adolescents and young adults with early psychosis through Supported Employment and Education (SEEearly): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Psychotic disorders often develop a chronic course with devastating consequences for individuals, families, and societies. Early intervention programs for people in the first 5 years after the initial psychotic episode (early psychosis) can significantly improve the outcome and are therefore strongly recommended in national and international guidelines. However, most early intervention programs still focus on improving symptoms and relapse prevention, rather than targeting educational and vocational recovery. The aim of the present study is to explore the effects of Supported Employment and Education (SEE) following the Individual Placement and Support (IPS) model in people with early psychosis. METHODS: The SEEearly trial compares treatment as usual (TAU) plus SEE to TAU alone in outpatient psychiatric settings. The study is a six-site, two-arm, single-blinded, superiority randomized controlled trial (RCT). Participants are randomly assigned (1:1) to the intervention or control group. Aiming to recruit 184 participants, with an assumed drop-out rate of 22%, we will be able to detect a 24% difference in the main outcome of employment/education with 90% power. We make assessments at baseline and at 6- and 12-month follow-ups. Outcome data on employment/education, medication, and current psychiatric treatment is obtained monthly through phone based short assessments. The primary outcome is steady participation for at least 50% of the 12-month follow-up in competitive employment and/or mainstream education. Secondary employment outcomes capture length of employment/education, time to first employment/education, monthly wages/educational attainment, and social return on investment (SROI). Secondary non-employment outcomes include subjective quality of life, psychopathology, substance use, relapse, hospitalization, and functional impairment. To be eligible, participants must be between 16 and 35 years, fulfill diagnostic criteria for early psychosis, and be interested in competitive employment and/or mainstream education. DISCUSSION: In SEEearly, we hypothesize that participants with psychosis, who receive TAU plus SEE, present with better primary and secondary outcomes than participants, who receive TAU alone. Positive results of this study will justify SEE as an evidence-based strategy for clinical routine treatment in people with early psychosis. TRIAL REGISTRATION: SEEearly was registered nationally and internationally in the German Clinical Trials Register (DRKS; identifier: DRKS00029660) on October 14, 2022.

[No improvement in live birth rate after luteal phase support by GnRH agonist]. / Absence d'amélioration du taux de naissance vivante après soutien de la phase lutéale par agoniste de la GnRH.

OBJECTIVES: To evaluate the impact of adding a GnRH agonist (GnRH-a) in luteal phase support (LPS) on live birth rates in IVF/ICSI in antagonist protocols. METHODS: In total, 341 IVF/ICSI attempts are analyzed in this retrospective study. Patients were divided into two groups: A f: LPS with progesterone alone (179 attempts) between March 2019 and May 2020; B: LPS with progesterone and an injection of triptorelin (GnRH-a) 0.1mg 6 days after oocyte retrieval (162 attempts) between June 2020 and June 2021. The primary outcome was live birth rate. The secondary outcomes were miscarriage rate, pregnancy rate and ovarian hyperstimulation syndrome rate. RESULTS: The baseline characteristic are identical between the two groups except the infertility duration (longer in the group B). There was no significant difference between the two groups in live birth rate (24.1% versus 21.2%), pregnancy rate (33.3% versus 28.1%), miscarriage rate (4.9% versus 3.4%) and no increase the SHSO rate. The multivariate regression analysis after adjustment for age, ovarian reserve and infertility duration did not reveal a significant difference in live birth rate between the two groups. CONCLUSION: In this study, the results showed no statistically significant association with the single injection of a GnRH-a in addition to progesterone on live birth rate in luteal phase support.

ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation.

OBJECTIVE: Chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction. Here we investigated the role of the adaptor protein Src homology and Collagen A (ShcA) in chondrocyte differentiation and osteoarthritis. METHODS: Mice ablated for ShcA in osteochondroprogenitor cells were generated by crossing mice carrying the Twist2-Cre transgene with ShcAflox/flox mice. Their phenotype (n = 5 to 14 mice per group) was characterized using histology, immuno-histology and western-blot. To identify the signaling mechanisms involved, in vitro experiments were conducted on wild type and ShcA deficient chondrocytes (isolated from n = 4 to 7 littermates) and the chondroprogenitor cell line ATDC5 (n = 4 independent experiments) using western-blot, cell fractionation and confocal microscopy. RESULTS: Deletion of ShcA decreases the hypertrophic zone of the growth plate (median between group difference -11.37% [95% confidence interval -17.34 to -8.654]), alters the endochondral ossification process, and leads to dwarfism (3 months old male mice nose-to-anus length -1.48 cm [-1.860 to -1.190]). ShcA promotes ERK1/2 activation, nuclear translocation of RunX2, the master transcription factor for chondrocyte hypertrophy, while maintaining the Runx2 inhibitor, YAP1, in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, loss of ShcA protects from age-related osteoarthritis development in mice (2 years old mice OARSI score -6.67 [-14.25 to -4.000]). CONCLUSION: This study reveals ShcA as a new player in the control of chondrocyte hypertrophic differentiation and its deletion slows down osteoarthritis development.

Behavioural, physical, and psychological predictors of cortisol and C-reactive protein in breast cancer survivors: A longitudinal study.

BACKGROUND: Breast cancer survivors (BCS) can exhibit a dysregulation of cortisol and elevated C-reactive protein (CRP) levels post-treatment, which increase the risk of diverse health outcomes. Certain behavioural, physical, and psychological variables may help to predict cortisol and CRP levels post-treatment. The aims of this study were to: (1) describe naturally occurring changes in absolute diurnal cortisol and CRP levels over a period of 1.5 years post-treatment among BCS, (2) assess if absolute diurnal cortisol and CRP levels change in tandem, and (3) assess behavioural, physical, and psychological variables as predictors of absolute diurnal cortisol levels and CRP levels. METHODS: Capillary blood and saliva samples were collected from 201 BCS, on average, 3.5 months post-treatment (T1) and again 3, 6, 9, and 12 months later (T2-T5). At each time point, five saliva samples were collected on two nonconsecutive days: at awakening, 30 â€‹min after awakening, 2:00 p.m., 4:00 p.m., and at bedtime. At each time point, participants also completed self-report questionnaires and wore an accelerometer for seven consecutive days. Data were analyzed using multilevel modeling. RESULTS: Absolute diurnal cortisol levels did not change significantly over time. CRP levels decreased across time points (B linear â€‹= â€‹-0.31, p â€‹= â€‹.01), though the rate of decrease slowed over time (B quadratic â€‹= â€‹0.05, p â€‹= â€‹.03). Generally, greater sedentary time predicted higher overall absolute diurnal cortisol levels (B â€‹< â€‹0.01, p â€‹= â€‹.01); whereas higher physical activity (B â€‹= â€‹-0.004, p â€‹< â€‹.01), lower body mass index (B â€‹= â€‹0.10, p â€‹< â€‹.01), and lower health- and cancer-related stress (B â€‹= â€‹0.24, p â€‹= â€‹.04) predicted lower overall CRP levels. Also, lower absolute diurnal cortisol levels were evident when participants engaged in more sedentary time, as compared to their own average sedentary time (B â€‹= â€‹-0.01, p â€‹< â€‹.01). CONCLUSIONS: Results offer insight into the nature of change in diurnal cortisol and CRP levels among BCS from treatment completion onwards and offer clinical implications. Helping BCS manage their weight, reduce stress, increase physical activity participation, and decrease sedentary time as soon as possible after treatment may help to reduce physiological dysregulations, thereby lowering the risk of adverse health outcomes in this population. Further research investigating specific intervention parameters such as type, context, frequency, and intensity are warranted for the development of the most optimal interventions.

[Genitourinary menopause syndrome. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. / Syndrome génito-urinaire de la ménopause (SGUM). RPC les femmes ménopausées du CNGOF et du GEMVi.

INTRODUCTION: Genitourinary menopause syndrome (SGUM) is defined as a set of symptoms associated with a decrease of estrogen and other sexual steroids during menopause. The main symptoms are vulvovaginal (dryness, burning, itching), sexual (dyspareunia), and urinary (urinary infections, pollakiuria, nycturia, pain, urinary incontinence by urgenturia). SGUM leads to an alteration of the quality of life, and affects especially women's sexuality. OBJECTIVE: The objective of this review was to elaborate guidelines for clinical practice regarding the management of SGUM in postmenopausal women, and in particular, in women with a history of breast cancer, treated or not with hormone therapy. MATERIALS AND METHODS: A systematic review of the literature on SGUM management was conducted on Pubmed, Medline and Cochrane Library. Recommendations from international scholarly societies were also taken into account: International Menopause Society (IMS) https://www.imsociety.org, The North American Menopause Society (NAMS) https://www.menopause.org, Canadian Menopause Society https://www.sigmamenopause.com, European Menopause and Andropause Society (EMAS) https://www.emas-online.org, International Society for the Study of Women's Sexual Health (ISSWSH) https://www.isswsh.org. RESULTS: Vaginal use of lubricants, moisturizers and hyaluronic acid improves the symptoms of SGUM and may be offered to all patients. For postmenopausal women, local estrogen will be preferred to the oral route because of their safety and efficacy on all symptoms of SGUM during low-dose use. Prasterone is a local treatment that can be proposed as an effective alternative for the management of dyspareunia and sexual function disorder. Current data on oral testosterone, tibolone, oral or transdermal DHEA and herbal medicine are currently limited. Ospemifène, which has shown a significant improvement in sexual symptoms, is not currently marketed in France. In the particular case of women with a history of breast cancer, non-hormonal regimens are a first-line therapy. Current data on the risk of breast cancer recurrence when administering low-dose local estrogen are reassuring but do not support a conclusion that this treatment is safe. CONCLUSION: SGUM is a common symptom that can affect the quality of life of postmenopausal women. A treatment should be systematically proposed. Local non-hormonal treatment may be offered in all women. Local low-dose estrogen therapy and Prasterone has shown an interest in the management of symptoms. In women before a history of breast cancer, local non-hormonal treatment should be offered first-line. The safety of low-dose local estrogen therapy and Prasterone cannot be established at this time. Other alternatives exist but are not currently recommended in France due to lack of data.

An investigation into socio-demographic-, health-, and cancer-related factors associated with cortisol and C-reactive protein levels in breast cancer survivors: a longitudinal study.

BACKGROUND: Breast cancer survivors (BCS) may exhibit dysregulated patterns of cortisol and C-reactive protein (CRP). The aims of this study were to describe BCS' cortisol and CRP levels over a 1-year period after treatment, and assess how levels relate to socio-demographic- (age, education level, marital status), health- (body mass index [BMI] category, menopausal status), and cancer-related factors (cancer stage, chemotherapy exposure, time since diagnosis). METHODS: Participants (N = 201) provided data at 3 months post-treatment (T1) and again 3, 6, 9, and 12 months later (T2-T5). At T1, participants completed self-report questionnaires and had their weight and height measured by a trained technician. At T1-T5, they provided five saliva samples at awakening, 30 min after awakening, 2:00 pm, 4:00 pm, and before bedtime on two nonconsecutive days to measure diurnal cortisol, and provided capillary whole blood to measure CRP. Data were analyzed using repeated-measure analyses of variance (ANOVAs) and mixed-design ANOVAs. RESULTS: Diurnal cortisol and CRP levels fluctuated over time. In univariate models, older age and post-menopausal status were associated with higher cortisol and CRP levels, higher cancer stage and chemotherapy were associated with lower cortisol levels, and higher BMI category was associated with higher CRP levels. In adjusted models, age was no longer associated with CRP levels and shorter time since diagnosis was significantly associated with higher CRP levels. CONCLUSIONS: Socio-demographic-, health-, and cancer-related factors may help identify BCS at risk of physiological dysregulation who need intervention. Identifying modifiable factors associated with cortisol and CRP will inform cancer care interventions.

Concomitant association of giant cell arteritis and malignancy: a multicenter retrospective case-control study.

INTRODUCTION: Some studies suggest that there is an increased risk of malignancies in giant cell arteritis (GCA). We aimed to describe the clinical characteristics and outcomes of GCA patients with concomitant malignancy and compare them to a GCA control group. METHOD: Patients with a diagnosis of GCA and malignancy and with a maximal delay of 12 months between both diagnoses were retrospectively included in this study and compared to a control group of age-matched (3:1) patients from a multicenter cohort of GCA patients. RESULTS: Forty-nine observations were collected (median age 76 years). Malignancies comprised 33 (67%) solid neoplasms and 16 (33%) clonal hematologic disorders. No over-representation of a particular type of malignancy was observed. Diagnosis of GCA and malignancy was synchronous in 7 (14%) patients, while malignancy succeeded GCA in 29 (59%) patients. Malignancy was fortuitously diagnosed based on abnormalities observed in laboratory tests in 26 patients, based on imaging in 14 patients, and based on symptoms or clinical examination in the nine remaining patients. Two patients had a concomitant relapse of both conditions. When compared to the control group, patients with concomitant GCA and malignancy were more frequently male (p < 0.001), with an altered general state (p < 0.001), and polymyalgia rheumatica (p < 0.01). CONCLUSIONS: This study does not indicate an over-representation of any particular type of malignancy in GCA patients. Initial follow-up dictated by vasculitis may have led to an early identification of malignancy. Nevertheless, GCA male patients with an altered general state and polymyalgia rheumatica might more frequently show concomitant malignancies.

Aerobic physical activity and salivary cortisol levels among women with a history of breast cancer.

BACKGROUND: Physical activity (PA) helps reduce cancer-related symptoms and improves overall functioning for women with and without a history of breast cancer (BC). Few researchers have examined the associations between PA and physiological stress measures. The aim of this study was to determine whether aerobic PA was associated with diurnal and reactive cortisol patterns, and whether these associations differed for women with and without a history of BC. METHODS: Participants were 25 women with a history of BC and 23 women without a history of BC who self-reported aerobic PA frequency. To assess diurnal cortisol patterns, participants provided five saliva samples collected on two consecutive days at the following times: upon awakening, 30 min after waking, 12 PM, 4 PM, and 9 PM. To measure reactive cortisol patterns, participants provided seven saliva samples collected before, during, and after doing the Trier Social Stress Test. RESULTS: Cortisol patterns differed statistically based on women's cancer history, whereby women without a history of BC had significantly higher overall cortisol reactivity to an acute stressor, and a marginally significant (p = .05) cancer experience by aerobic PA interaction was observed when analyzing diurnal cortisol data. CONCLUSIONS: Findings suggest that PA may not have the same effect on women with and without a history of BC.

[Contraception: CNGOF Guidelines for Clinical Practice (Short Version)]. / Contraception : Recommandations pour la Pratique Clinique du CNGOF (texte court).

The French College of Obstetrics and Gynecology (CNGOF) releases its first global recommendations for clinical practice in contraception, to provide physicians with an updated synthesis of available data as a basis for their practice. The French Health Authority (HAS) methodology was used. Twelve practical issues were selected by the organizing committee and the task force members. The available literature was screened until December 2017, and allowed the release of evidence-based, graded recommendations. This synthesis is issued from 12 developed texts, previously reviewed by experts and physicians from public and private practices, with an experience in the contraceptive field. Male and female sterilization, as well as the use of hormonal treatments without contraceptive label were excluded from the field of this analysis. Specific practical recommendations on the management of contraception prescription, patient information including efficacy, risks, and benefits of the different contraception methods, follow up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers and after 40, contraception in vascular high-risk situations, and in case of cancer risk are provided. The short/mid-term future of contraception mostly relies on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, whatever the social and clinical context. That is the goal of these recommendations.

Head-to-head trials of antibiotics for bronchiectasis.

BACKGROUND: The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer-term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost-effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions. OBJECTIVES: To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies. SELECTION CRITERIA: We included RCTs reported as full-text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high-resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs). MAIN RESULTS: Four randomised trials were eligible for inclusion in this systematic review - two studies with 83 adults comparing fluoroquinolones with ß-lactams and two studies with 55 adults comparing aminoglycosides with polymyxins.None of the included studies reported information on exacerbations - one of our primary outcomes. Included studies reported no serious adverse events - another of our primary outcomes - and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and ß-lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low-quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low-quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low-quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV1). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low-quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low-quality evidence). The evidence for changes in FEV1 was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. AUTHORS' CONCLUSIONS: Limited low-quality evidence favours short-term oral fluoroquinolones over beta-lactam antibiotics for patients hospitalised with exacerbations. Very low-quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head-to-head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short-term or long-term therapy. More research on this topic is needed.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

Continuous versus intermittent antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic airway disease characterised by a destructive cycle of recurrent airway infection, inflammation and tissue damage. Antibiotics are a main treatment for bronchiectasis. The aim of continuous therapy with prophylactic antibiotics is to suppress bacterial load, but bacteria may become resistant to the antibiotic, leading to a loss of effectiveness. On the other hand, intermittent prophylactic antibiotics, given over a predefined duration and interval, may reduce antibiotic selection pressure and reduce or prevent the development of resistance. This systematic review aimed to evaluate the current evidence for studies comparing continuous versus intermittent administration of antibiotic treatment in bronchiectasis in terms of clinical efficacy, the emergence of resistance and serious adverse events. OBJECTIVES: To evaluate the effectiveness of continuous versus intermittent antibiotics in the treatment of adults and children with bronchiectasis, using the primary outcomes of exacerbations, antibiotic resistance and serious adverse events. SEARCH METHODS: On 1 August 2017 and 4 May 2018 we searched the Cochrane Airways Review Group Specialised Register (CAGR), CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. On 25 September 2017 and 4 May 2018 we also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal, conference proceedings and the reference lists of existing systematic reviews. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) of adults or children with bronchiectasis that compared continuous versus intermittent administration of long-term prophylactic antibiotics of at least three months' duration. We considered eligible studies reported as full-text articles, as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and full-text reports. MAIN RESULTS: We identified 268 unique records. Of these we retrieved and examined 126 full-text reports, representing 114 studies, but none of these studies met our inclusion criteria. AUTHORS' CONCLUSIONS: No randomised controlled trials have compared the effectiveness and risks of continuous antibiotic therapy versus intermittent antibiotic therapy for bronchiectasis. High-quality clinical trials are needed to establish which of these interventions is more effective for reducing the frequency and duration of exacerbations, antibiotic resistance and the occurrence of serious adverse events.

Dual antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation of the smaller airways and associated with a mortality rate greater than twice that of the general population. Antibiotics serve as front-line therapy for managing bacterial load, but their use is weighed against the development of antibiotic resistance. Dual antibiotic therapy has the potential to suppress infection from multiple strains of bacteria, leading to more successful treatment of exacerbations, reduced symptoms, and improved quality of life. Further evidence is required on the efficacy of dual antibiotics in terms of management of exacerbations and extent of antibiotic resistance. OBJECTIVES: To evaluate the effects of dual antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified studies from the Cochrane Airways Group Specialised Register (CAGR), which includes the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine (AMED), and PsycINFO, as well as studies obtained by handsearching of journals/abstracts. We also searched the following trial registries: US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. We imposed no restriction on language of publication. We conducted our search in October 2017. SELECTION CRITERIA: We searched for randomised controlled trials comparing dual antibiotics versus a single antibiotic for short-term (< 4 weeks) or long-term management of bronchiectasis diagnosed in adults and/or children by bronchography, plain film chest radiography, or high-resolution computed tomography. Primary outcomes included exacerbations, length of hospitalisation, and serious adverse events. Secondary outcomes were response rates, emergence of resistance to antibiotics, systemic markers of infection, sputum volume and purulence, measures of lung function, adverse events/effects, deaths, exercise capacity, and health-related quality of life. We did not apply outcome measures as selection criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 287 records, along with the full text of seven reports. Two studies met review inclusion criteria. Two review authors independently extracted outcome data and assessed risk of bias. We extracted data from only one study and conducted GRADE assessments for the following outcomes: successful treatment of exacerbation; response rates; and serious adverse events. MAIN RESULTS: Two randomised trials assessed the effectiveness of oral plus inhaled dual therapy versus oral monotherapy in a total of 118 adults with a mean age of 62.8 years. One multi-centre trial compared inhaled tobramycin plus oral ciprofloxacin versus ciprofloxacin alone, and one single-centre trial compared nebulised gentamicin plus systemic antibiotics versus a systemic antibiotic alone. Published papers did not report study funding sources.Effect estimates from one small study with 53 adults showed no evidence of treatment benefit with oral plus inhaled dual therapy for the following primary outcomes at the end of the study: successful management of exacerbation - cure at day 42 (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.22 to 2.01; 53 participants; one study; very low-quality evidence); number of participants with Pseudomonas aeruginosa eradication at day 21 (OR 2.33, 95% CI 0.66 to 8.24; 53 participants; one study; very low-quality evidence); and serious adverse events (OR 0.48, 95% CI 0.08 to 2.87; 53 participants; one study; very low-quality evidence). Similarly, researchers provided no evidence of treatment benefit for the following secondary outcomes: clinical response rates - relapse at day 42 (OR 0.57, 95% CI 0.12 to 2.69; 53 participants; one study; very low-quality evidence); microbiological response rate at day 21 - eradicated (OR 2.40, 95% CI 0.67 to 8.65; 53 participants; one study; very low-quality evidence); and adverse events - incidence of wheeze (OR 5.75, 95% CI 1.55 to 21.33). Data show no evidence of benefit in terms of sputum volume, lung function, or antibiotic resistance. Outcomes from a second small study with 65 adults, available only as an abstract, were not included in the quantitative data synthesis. The included studies did not report our other primary outcomes: duration; frequency; and time to next exacerbation; nor our secondary outcomes: systemic markers of infection; exercise capacity; and quality of life. We did not identify any trials that included children. AUTHORS' CONCLUSIONS: A small number of studies in adults have generated high-quality evidence that is insufficient to inform robust conclusions, and studies in children have provided no evidence. We identified only one dual-therapy combination of oral and inhaled antibiotics. Results from this single trial of 53 adults that we were able to include in the quantitative synthesis showed no evidence of treatment benefit with oral plus inhaled dual therapy in terms of successful treatment of exacerbations, serious adverse events, sputum volume, lung function, and antibiotic resistance. Further high-quality research is required to determine the efficacy and safety of other combinations of dual antibiotics for both adults and children with bronchiectasis, particularly in terms of antibiotic resistance.

Oral versus inhaled antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic inflammatory disease characterised by a recurrent cycle of respiratory bacterial infections associated with cough, sputum production and impaired quality of life. Antibiotics are the main therapeutic option for managing bronchiectasis exacerbations. Evidence suggests that inhaled antibiotics may be associated with more effective eradication of infective organisms and a lower risk of developing antibiotic resistance when compared with orally administered antibiotics. However, it is currently unclear whether antibiotics are more effective when administered orally or by inhalation. OBJECTIVES: To determine the comparative efficacy and safety of oral versus inhaled antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified studies through searches of the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Information Specialist for the group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched ClinicalTrials.gov and the WHO trials portal. We searched all databases in March 2018 and imposed no restrictions on language of publication. SELECTION CRITERIA: We planned to include studies which compared oral antibiotics with inhaled antibiotics. We would have considered short-term use (less than four weeks) for treating acute exacerbations separately from longer-term use as a prophylactic (4 weeks or more). We would have considered both intraclass and interclass comparisons. We planned to exclude studies if the participants received continuous or high-dose antibiotics immediately before the start of the trial, or if they have received a diagnosis of cystic fibrosis (CF), sarcoidosis, active allergic bronchopulmonary aspergillosis or active non-tuberculous Mycobacterial infection. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria to the searches and we planned for two authors to independently extract data, assess risk of bias and assess overall quality of the evidence using GRADE criteria. We also planned to obtain missing data from the authors where possible and to report results with 95% confidence intervals (CIs). MAIN RESULTS: We identified 313 unique records through database searches and a further 21 records from trial registers. We excluded 307 on the basis of title and abstract alone and a further 27 after examining full-text reports. No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS: There is currently no evidence indicating whether orally administered antibiotics are more beneficial compared to inhaled antibiotics. The recent ERS bronchiectasis guidelines provide a practical approach to the use of long-term antibiotics. New research is needed comparing inhaled versus oral antibiotic therapies for bronchiectasis patients with a history of frequent exacerbations, to establish which approach is the most effective in terms of exacerbation prevention, quality of life, treatment burden, and antibiotic resistance.

Macrolide antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance. OBJECTIVES: To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children. AUTHORS' CONCLUSIONS: Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia.

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

Langerhans cell: exciting developments in health and disease.

Langerhans cells (LCs) have been the subject of much research since their discovery in 1868. LCs belong to the subset of leucocytes called dendritic cells. They are present in the epidermis and the pilosebaceous apparatus and monitor the cutaneous environment for changes in homeostasis. During embryogenesis, a wave of yolk sac macrophages seed the fetal skin. Then, fetal liver monocytes largely replace the yolk sac macrophages and comprise the majority of adult LCs. In the presence of skin irritation, LCs process antigen and travel to regional lymph nodes to present antigen to reactive T lymphocytes. Changes in LCs' surface markers during the journey occur under the influence of cytokines. The difference in expression of surface markers and the ability to resist radiation have allowed researchers to differentiate LCs from the murine Langerin-positive dermal dendritic cells. Exciting discoveries have been made recently regarding their role in inflammatory skin diseases, cancer and HIV. New research has shown that antibodies blocking CD1a appear to mitigate inflammation in contact hypersensitivity reactions and psoriasis. While it has been established that LCs have the potential to induce effector cells of the adaptive immune system to counter oncogenesis, recent studies have demonstrated that LCs coordinate with natural killer cells to impair development of squamous cell carcinoma caused by chemical carcinogens. However, LCs may also physiologically suppress T cells and permit keratinocyte transformation and tumorigenesis. Although long known to play a primary role in the progression of HIV infection, it is now understood that LCs also possess the ability to restrict the progression of the disease. There is a pressing need to discover more about how these cells affect various aspects of health and disease; new information gathered thus far seems promising and exciting.