Treatment of adult attention-deficit hyperactivity disorder (ADHD) with transcranial direct current stimulation (tDCS): study protocol for a parallel, randomized, double-blinded, sham-controlled, multicenter trial (Stim-ADHD).

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners' Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.Trial Registration The trial was registered on July 29, 2022 in the German Clinical Trials Register (DRKS00028148).

Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery will be eligible. Two hun-dred forty patients will be randomly assigned (1:1) to either standard aRCT with cisplatin (standard arm) or aRCT with cisplatin + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months) (interventional arm). Endpoints are event-free and overall survival. Recruitment started in August 2018 and is ongoing.

Nasal high-flow compared to non-invasive ventilation in treatment of acute acidotic hypercapnic exacerbation of chronic obstructive pulmonary disease-protocol for a randomized controlled noninferiority trial (ELVIS).

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have a major negative impact on health status, rates of hospitalization, readmission, disease progression and mortality. Non-invasive ventilation (NIV) is the standard therapy for hypercapnic acidotic respiratory failure in AECOPD. Despite its beneficial effects, NIV is often poorly tolerated (11-34 % failure rate). An increasing number of studies have documented a beneficial effect of nasal high-flow (NHF) in acute hypercapnia. We designed a prospective, randomized, multi-centre, open label, non-inferiority trial to compare treatment failure in nasal NHF vs NIV in patients with acidotic hypercapnic AECOPD. METHODS: The study will be conducted in about 35 sites in Germany. Patients with hypercapnic AECOPD with respiratory acidosis (pH < 7.35) will be randomized 1:1 to NIV or NHF. The primary outcome is the combined endpoint of intubation, treatment failure or death at 72 h. The switch from one to the other device marks a device failure but acts as a rescue treatment in absence of intubation criteria. A sample size of 720 was calculated to have 80% power for showing that NHF is non-inferior to NIV with a margin of 8 percentage points. Linear regression will be used for the confirmatory analysis. DISCUSSION: If NHF is shown to be non-inferior to NIV in acidotic hypercapnic AECOPD, it could become an important alternative treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04881409 , Registered on May 11, 2021.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Bromocriptine treatment in patients with peripartum cardiomyopathy and right ventricular dysfunction.

BACKGROUND: Right ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement. METHODS: In this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF < 45%). We examined the effect of short-term (1W: bromocriptine, 2.5 mg, 7 days, n = 10) compared with long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for another 6 weeks, n = 14) in addition to guideline-based heart failure therapy in patients with an initial RVEF < 45% on the following outcomes: (1) change from baseline (Δ delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF ≥ 50%) and (4) rate of patients with full RV recovery (RVEF ≥ 55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging. RESULTS: Reduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up (patients with RV dysfunction: 58% vs. patients with normal RV function: 81%; p = 0.027). RVEF increased from 38 ± 7 to 53 ± 11% with a delta-RVEF of + 15 ± 12% in the 1W group, and from 35 ± 9 to 58 ± 7% with a Δ RVEF of + 23 ± 10% in the 8W group (Δ RVEF 1W vs 8W: p = 0.118). LVEF increased from 25 ± 8 to 46 ± 12% with a Δ LVEF of + 21 ± 11% in the 1W group, and from 22 ± 6 to 49 ± 10% with a Δ LVEF of + 27 ± 9% in the 8W group (Δ LVEF 1W vs 8W: p = 0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p = 0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p = 0.092). CONCLUSIONS: Despite overall worse outcome in patients with RV dysfunction at baseline, bromocriptine treatment in PPCM patients with RV involvement was associated with a high rate of full RV and LV recovery, although no significant differences were observed between the short-term and long-term bromocriptine treatment regime. These findings suggest that bromocriptine in addition to standard heart failure therapy may be also effective in PPCM patients with biventricular impairment.

Cognitive correlates of α4ß2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4ß2 nicotinic acetylcholine receptors (α4ß2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4ß2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4ß2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4ß2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4ß2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4ß2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4ß2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4ß2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4ß2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.

Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study.

AIMS: An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM. METHODS AND RESULTS: In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died. CONCLUSION: Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, study number: NCT00998556.

The BASALIT multicenter trial: Gly m 4 quantification for consistency control of challenge meal batches and toward Gly m 4 threshold data.

SCOPE: The BASALIT clinical trial (EudraCT 2009-011737-27) investigated efficacy of birch allergen immunotherapy on lowest observed adverse effect levels after soy food challenge in patients with birch-associated and Gly m 4 allergen mediated soy allergy. Thus, consistently stable Gly m 4 levels were required in standardized challenge meals. METHODS AND RESULTS: Soy meal included soy protein isolate (SPI, 88% total protein). A Gly m 4 specific ELISA was developed and validated. Six SPIs and 24 meal batches were analyzed for Gly m 4. (Repeated-measures) analyses of variance were done to identify potential changes between batches and time intervals. Gly m 4 was below the ELISA detection limit (2 ng/mL) in placebo batches. With <20% mean coefficient of variation, Gly m 4 levels were consistent in 24 soy meal batches and within individual 12-wk shelf-life. CONCLUSION: The novel Gly m 4 specific ELISA proved consistency of challenge meal batches over a 56-month study period. With an average of 178 µg/g Gly m 4 in SPI, Gly m 4 lowest observed adverse effect level can be calculated once clinical lowest observed adverse effect level data based on SPI are available. Hence, sensitivity of patients can be correlated to the relevant allergen content instead of total protein of the allergenic source.

Measurement of health-related quality of life in adult patients with birch pollen-associated food allergy.

BACKGROUND: The "Food Allergy Quality of Life Questionnaire - Adult Form" (FAQLQ-AF) is the first freely available questionnaire for the assessment of health-related quality of life (HRQL) in adults with food allergy (FA). We present validation data for the German version as well as data on HRQL in patients with birch pollen-associated FA. PATIENTS AND METHODS: The Dutch FAQLQ-AF (scale from 1-7, no impairment - maximum impairment) was translated into German. Subsequently, 73 consecutive patients with a history of birch pollen-associated FA (52 women, median age 43 years) were surveyed using questions regarding triggers and symptoms of their FA as well as questions contained in the FAQLQ-AF. Construct validity, internal consistency, and discriminative ability were analyzed. RESULTS: The foods most frequently reported to elicit allergic reactions included apple (78%), hazelnut (75%), soy drinks (55%), and carrot (52%). Thirty percent of patients exclusively reported symptoms consistent with oral allergy syndrome (OAS). Sixty-four percent reported OAS combined with systemic symptoms, and only 6% were exclusively affected by non-OAS symptoms. The German FAQLQ-AF showed good construct validity (correlation with the food allergy-independent measure: r = 0.81; p < 0.001) and excellent internal consistency (Cronbachs α = 0.98). The mean overall FAQLQ-AF score was 3.7. Women, elderly individuals, and those with multiple relevant food allergies showed a greater impairment of HRQL. CONCLUSIONS: The German FAQLQ-AF questionnaire is a reliable and valid tool for measuring HRQL in patients with birch pollen-associated food allergy.

First-in-human PET quantification study of cerebral α4ß2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.

α4ß2* nicotinic receptors (α4ß2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of α4ß2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (-)-[(18)F]Flubatine, formerly known as (-)-[(18)F]NCFHEB, as a tool for α4ß2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (-)-[(18)F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm(3)), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of α4ß2* receptors (VT [thalamus] 27.4±3.8, VT [putamen] 12.7±0.9, VT [frontal cortex] 10.0±0.8, and VT [corpus callosum] 6.3±0.8). The BPND, which is a parameter of α4ß2* nAChR availability, was 3.41±0.79 for the thalamus, 1.04±0.25 for the putamen and 0.61±0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-)-[(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4ß2* nAChRs in neuropsychiatric disorders.

Percutaneous ethanol injection or percutaneous acetic acid injection for early hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common global cancer. When HCC is diagnosed early, interventions such as percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), or radiofrequency (thermal) ablation (RF(T)A) may have curative potential and represent less invasive alternatives to surgery. OBJECTIVES: To evaluate the beneficial and harmful effects of PEI or PAI in adults with early HCC defined according to the Milan criteria, that is, one cancer nodule up to 5 cm in diameter or up to three cancer nodules up to 3 cm in diameter compared with no intervention, sham intervention, each other, other percutaneous interventions, or surgery. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (July 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1946 to July 2014), EMBASE (1976 to July 2014), and Science Citation Index Expanded (1900 to July 2014). We handsearched meeting abstracts of six oncological and hepatological societies and references of articles to July 2014. We contacted researchers in the field. SELECTION CRITERIA: We considered randomised clinical trials comparing PEI or PAI versus no intervention, sham intervention, each other, other percutaneous interventions, or surgery for the treatment of early HCC regardless of blinding, publication status, or language. We excluded studies comparing RFA or combination of different interventions as such interventions have been or will be addressed in other Cochrane Hepato-Biliary Group systematic reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, and extracted and analysed data. We calculated the hazard ratios (HR) for median overall survival and recurrence-free survival using the Cox regression model with Parmar's method. We reported type and number of adverse events descriptively. We assessed risk of bias by The Cochrane Collaboration domains to reduce systematic errors and risk of play of chance by trial sequential analysis to reduce random errors. We assessed the methodological quality with GRADE. MAIN RESULTS: We identified three randomised trials with 261 participants for inclusion. The risk of bias was low in one and high in two trials.Two of the randomised trials compared PEI versus PAI; we included 185 participants in the analysis. The overall survival (HR 1.47; 95% confidence interval (CI) 0.68 to 3.19) and recurrence-free survival (HR 1.42; 95% CI 0.68 to 2.94) were not statistically significantly different between the intervention groups of the two trials. Trial sequential analysis for the comparison PEI versus PAI including two trials revealed that the number of participants that were included in the trials were insufficient in order to judge a relative risk reduction of 20%. Data on the duration of hospital stay were available from one trial for the comparison PEI versus PAI showing a significantly shorter hospital stay for the participants treated with PEI (mean 1.7 days; range 2 to 3 days) versus PAI (mean 2.2 days; range 2 to 5 days). Quality of life was not reported. There were only mild adverse events in participants treated with either PEI or PAI such as transient fever, flushing, and local pain.One randomised trial compared PEI versus surgery; we included 76 participants in the analyses. There was no significant difference in the overall survival (HR 1.57; 95% CI 0.53 to 4.61) and recurrence-free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group while three postoperative deaths occurred in the surgery group.In addition to the three randomised trials, we identified one quasi-randomised study comparing PEI versus PAI. Due to methodological flaws of the study, we extracted only the data on adverse events and presented them in a narrative way.We found no randomised trials that compared PEI or PAI versus no intervention, best supportive care, sham intervention, or other percutaneous local ablative therapies excluding RFTA. We found also no randomised clinical trials that compared PAI versus other interventional treatments or surgery. We identified two ongoing randomised clinical trials. One of these two trials compares PEI versus surgery and the other PEI versus transarterial chemoembolization. To date, it is unclear whether the trials will be eligible for inclusion in this meta-analysis as the data are not yet available. This review will not be updated until new randomised clinical trials are published and can be used for analysis. AUTHORS' CONCLUSIONS: PEI versus PAI did not differ significantly regarding benefits and harms in people with early HCC, but the two included trials had only a limited number of participants and one trial was judged a high risk of bias. Thus, the current evidence precludes us from making any firm conclusions.There was also insufficient evidence to determine whether PEI versus surgery (segmental liver resection) was more effective, because conclusions were based on a single randomised trial. While some data from this single trial suggested that PEI was safer, the high risk of bias and the lack of any confirmatory evidence make a reliable assessment impossible.We found no trials assessing PEI or PAI versus no intervention, best supportive care, or sham intervention.There is a need for more randomised clinical trials assessing interventions for people with early stage HCC. Such trials should be conducted with low risks of systematic errors and random errors.

Early peripheral laser photocoagulation of nonperfused retina improves vision in patients with central retinal vein occlusion (Results of a proof of concept study).

BACKGROUND: To evaluate the effect of combination of ranibizumab and laser photocoagulation to peripheral retinal areas of nonperfusion in patients with non-ischemic central retinal vein occlusion (CRVO) without neovascularizations. METHODS: This prospective, proof of concept study randomized 22 CRVO patients into two arms. The RL group (ranibizumab + laser; n = 10) received ranibizumab with additive laser photocoagulation; the control R group (n = 12) was treated with ranibizumab only. All patients received three initial monthly ranibizumab injections followed by PRN regimen. Changes in best corrected visual acuity (BCVA) and in central retinal thickness (CRT) were documented over 6 months. RESULTS: Median of BCVA improved in the RL group from 65 ETDRS letters (interquartile range IQR = 10 letters) at baseline to 70 (IQR = 23.2) letters at month 6. In the control group BCVA remained stable [baseline: 61 (IQR = 19.5) and month 6: 61 (IQR = 22) letters]. CRT decreased between baseline and final visit in the RL group from 547 (IQR = 513) µm to 246.5 (IQR = 346.3) µm, and in the control group from 637.5 (IQR = 344) µm to 423 (IQR = 737) µm. More pronounced improvements in BCVA were seen in the RL group (medians = 14 vs. 6.5 letters) although the observed group differences were not statistically significant due to small samples. CONCLUSIONS: The selective laser photocoagulation of peripheral areas of nonperfusion seems to lead to additional visual improvement in patients with CRVO. A larger replication trial is necessary to confirm the results of this proof of concept study.

Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the fifth most common cancer worldwide. Percutaneous interventional therapies, such as radiofrequency (thermal) ablation (RFA), have been developed for early hepatocellular carcinoma. RFA competes with other interventional techniques such as percutaneous ethanol injection, surgical resection, and liver transplantation. The potential benefits and harms of RFA compared with placebo, no intervention, chemotherapy, hepatic resection, liver transplantation, or other interventions are unclear. OBJECTIVES: To assess the beneficial and harmful effects of RFA versus placebo, no intervention, or any other therapeutic approach in patients with hepatocellular carcinoma. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science to September 2012. We handsearched meeting abstracts from ASCO, ESMO, AASLD, EASL, APASL, and references of articles. We also contacted researchers in the field (last search September 2012). SELECTION CRITERIA: We considered for inclusion randomised clinical trials investigating the effects of RFA versus placebo, no intervention, or any other therapeutic approach on hepatocellular carcinoma patients regardless of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the selection of trials, assessment of risk of bias, and data extraction. We contacted principal investigators for missing information. We analysed hazard ratios (HR) as relevant effect measures for overall survival, two-year survival, event-free survival, and local recurrences with 95% confidence intervals (CI). In addition, we analysed dichotomous survival outcomes using risk ratios (RR). We used trial sequential analysis to control the risk of random errors ('play of chance'). MAIN RESULTS: We identified no trials comparing RFA versus placebo, no intervention, or liver transplantation. We identified and included 11 randomised clinical trials with 1819 participants that included four comparisons: RFA versus hepatic resection (three trials, 578 participants); RFA versus percutaneous ethanol injection (six trials, 1088 participants) including one three-armed trial that also investigated RFA versus acetic acid injection; RFA versus microwave ablation (one trial, 72 participants); and RFA versus laser ablation (one trial, 81 participants). Ten of the eleven included trials reported on the primary outcome of this review, overall survival. Rates of major complications or procedure-related deaths were reported in 10 trials. The overall risk of bias was considered low in five trials and high in six trials. For a subgroup analysis, we included only low risk of bias trials. Regarding the comparison RFA versus hepatic resection, there was moderate-quality evidence from two low risk of bias trials that hepatic resection seems more effective than RFA regarding overall survival (HR 0.56; 95% CI 0.40 to 0.78) and two-year survival (HR 0.38; 95% CI 0.17 to 0.84). However, if we included a third trial with high risk of bias, the difference became insignificant (overall survival: HR 0.71; 95% CI 0.44 to 1.15). With regards to the outcomes event-free survival and local progression, hepatic resection also yielded better results than RFA. However, the number of complications was higher in surgically treated participants (odds ratio (OR) 8.24; 95% CI 2.12 to 31.95). RFA seemed superior to percutaneous ethanol or acetic acid injection regarding overall survival (HR 1.64; 95% CI 1.31 to 2.07). The RR for mortality was also in favour of RFA, but did not reach statistical significance (150/490 (30.6%) people in the percutaneous ethanol or acetic acid group versus 119/496 (24.0%) people in the RFA group; RR 1.76; 95% CI 0.97 to 3.22). The proportion of adverse events did not differ significantly between RFA and percutaneous ethanol or acetic acid injection (HR 0.70; 95% CI 0.33 to 1.48). Trial sequential analyses revealed that the number of participants in the included trials was insufficient and that more trials are needed to assess the effects of RFA versus other interventions. AUTHORS' CONCLUSIONS: The effects of RFA versus no intervention, chemotherapeutic treatment, or liver transplantation are unknown. We found moderate-quality evidence that hepatic resection is superior to RFA regarding survival. However, RFA might be associated with fewer complications and a shorter hospital stay than hepatic resection. We found moderate-quality evidence showing that RFA seems superior to percutaneous ethanol injection regarding survival. There were too sparse data to recommend or refute ablation achieved by techniques other than RFA. More randomised clinical trials with low risk of bias and low risks of random errors assessing the effect of RFA are needed.

The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder.

The pathogenetic role of central serotonin transporters (SERT) in obsessive-compulsive disorder (OCD) has been investigated in vivo by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) studies with inconsistent results. This might reflect methodological differences but possibly also the pathophysiological heterogeneity of the disorder, i.e. the age at onset of OCD. The aim of our study was to compare SERT availability in patients with OCD to healthy controls (HC) taking into account the onset type, other factors and covariates (e.g. SERT genotype, age, depression level, gender). We studied 19 drug-naive OCD patients (36±13 yr, eight females) with early onset (EO-OCD, n=6) or with late onset (LO-OCD, n=13), and 21 HC (38±8 yr, nine females) with PET and the SERT-selective radiotracer [11C]DASB. Statistical models indicated that a variety of covariates and their interaction influenced SERT availability measured by distribution volume ratios (DVR). These models revealed significant effects of onset type on DVR with lower values in LO-OCD (starting at age 18 yr) compared to EO-OCD and HC in limbic (e.g. the amygdala), paralimbic brain areas (the anterior cingulate cortex), the nucleus accumbens and striatal regions, as well as borderline significance in the thalamus and the hypothalamus. The putamen, nucleus accumbens and hypothalamus were found with significant interaction between two SERT gene polymorphisms (SERT-LPR and VNTR). These findings suggest that late but not early onset of OCD is associated with abnormally low SERT availability. In part, functional polymorphisms of the SERT gene might determine the differences.

ST-segment resolution and prognosis after facilitated versus primary percutaneous coronary intervention in acute myocardial infarction: a meta-analysis.

BACKGROUND: Complete ST-segment resolution (STR) is associated with favorable prognosis in ST-elevation myocardial infarction (STEMI). The optimal reperfusion strategy in patients with STEMI presenting early after symptom-onset is still a matter of debate. So far, there are only a few studies comparing the effect of facilitated and primary percutaneous coronary intervention (PCI) on early myocardial reperfusion assessed by STR. The objective of this meta-analysis was, therefore, to evaluate the extent of early STR and subsequent prognosis in facilitated versus primary PCI. METHODS: From 1990 to 2008, we identified 14 trials of patients with STEMI reporting STR data assigned to facilitated or primary PCI. The primary endpoint of this pooled analysis was STR before and after PCI. Clinical efficacy outcomes included short-term all-cause mortality at 30-90 days and mortality after 6 months. RESULTS: Together, these 14 trials randomly assigned 6,439 patients (3,605 to facilitated PCI, 2,834 to primary PCI). The facilitation agents were platelet glycoprotein IIb/IIIa inhibitors in nine (1,589 patients), fibrinolysis in three (1,037 patients), and the combination of platelet glycoprotein IIb/IIIa inhibitors plus reduced-dose fibrinolysis in three trials (979 patients). STR data were available in 4,105 patients (2,215 facilitated PCI, 1,890 primary PCI). Patients undergoing facilitated PCI were significantly more likely to achieve STR before catheterization and after PCI [OR pre-PCI 1.59 (CI 1.3, 1.90); OR post-PCI 1.69 (CI 1.28, 2.24)]. Despite this significantly improved surrogate parameter of effective myocardial reperfusion, mortality was similar between groups [OR 1.11 (CI 0.84, 1.45)]. CONCLUSIONS: Prehospital initiated facilitated PCI results in a higher percentage of complete STR before and after PCI when compared with primary PCI. However, this enhanced early reperfusion did not significantly improve the outcome after facilitated PCI. Therefore, the current data suggest that facilitated PCI does not offer an advantage over primary PCI. The results from ongoing clinical trials in STEMI patients presenting early (<3 h) after symptom-onset with more effective antithrombotic co-therapy will provide guidance regarding the utility of a facilitated PCI strategy.

Evaluation of the efficacy of subcutaneous carbon dioxide insufflations for treating acute non specific neck pain in general practice: A sham controlled randomized trial.

BACKGROUND: Subcutaneous carbon dioxide insufflations are a safe and inexpensive treatment modality in complementary medicine and are used mainly in musculoskeletal pain and vascular conditions. However, no rigorous trial exists on their efficacy. AIMS: To evaluate whether patients with acute non specific neck pain get pain free sooner, if treated with subcutaneous carbon dioxide insufflations compared to sham ultrasound. METHODS: One hundred and twenty-six persons from one German general practice with acute non specific neck pain less than 7 days and a current pain intensity 40 mm on a 100 mm visual analogue scale were included into the trial. Participants received either a maximum number of nine subcutaneous carbon dioxide insufflations or a maximum number of nine sham ultrasound administered by four therapists in a randomized order, thrice weekly. Main outcome measure was time to neck pain relief during a 28 days follow-up period from baseline analyzed by intention to treat. RESULTS: Twenty-seven of 63 patients (43%) got neck pain free in the subcutaneous carbon dioxide insufflations group compared to 29 of 63 (46%) in the sham ultrasound group. Median time to neck pain relief was 28 days in both groups (p=.77; logrank test). Secondary analyses yielded similar results. CONCLUSIONS: The study indicates that subcutaneous carbon dioxide insufflations are not superior to sham ultrasound for treating patients with acute non specific neck pain. Because course of pain did not differ from the one expected from self limitation, it is likely that non specific effects played only a minor role, if any, in both interventions.

A pragmatic randomized controlled trial on the effectiveness of highly concentrated saline spa water baths followed by UVB compared to UVB only in moderate to severe psoriasis.

BACKGROUND: There is a lack of sufficiently large randomized trials evaluating the effectiveness of saline spa balneophototherapy compared to ultraviolet B (UVB) only. OBJECTIVE: The study aimed to evaluate whether highly concentrated saline spa water baths followed by UVB (HC-SSW-UVB) are superior to UVB only in moderate to severe psoriasis. METHODS: One hundred and sixty (160) adults with a Psoriasis Area and Severity Index (PASI) of >10 from 4 German spa centers were randomly allocated to HC-SSW-UVB (local sodium chloride concentration between 25% and 27%) or UVB only 3 a week until remission (PASI < 5) or for a maximum of 6 weeks. Reduction of PASI > or = 50% (PASI-50) at the end of the intervention period was defined as primary outcome. Only persons receiving at least 1 intervention were included into the primary analysis. RESULTS: Participants allocated to HC-SSW-UVB attained to a statistically significantly higher rate of PASI-50 than patients allocated to UVB only (68/79 [86%] versus 38/71 [54%]; p < 0.001; number needed to treat, 3.1; 95% confidence interval, 2.1-6.0). Postintervention analysis did not yield a clear hint of a persisting effect. CONCLUSIONS: The study indicates that HC-SSW-UVB are superior to routine UVB at the end of a 6-week treatment course.

Bath PUVA and saltwater baths followed by UV-B phototherapy as treatments for psoriasis: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of psoralens dissolved in a warm-water bath followed by exposure to UV-A irradiation (bath PUVA) or saltwater phototherapy (SW UV-B) compared with tap-water phototherapy (TW UV-B) or UV-B irradiation alone in psoriasis. DESIGN: Multisite, prospective, randomized, controlled trial with 4 parallel groups. SETTING: Total of 102 dermatologic outpatient clinics. PATIENTS: Total of 1241 patients with stable psoriasis vulgaris and a Psoriasis Area and Severity Index score of 7 or greater. INTERVENTIONS: Four-times-weekly UV-B, TW UV-B, SW UV-B, or bath-PUVA with baths preceding UV irradiation over a maximum of 8 weeks. The UV dose was adapted to erythemal response. MAIN OUTCOME MEASURES: Incidence of therapeutic success, defined as a reduction of the Psoriasis Area and Severity Index or affected body surface area of 50% or more. RESULTS: Patients who received TW UV-B had a significantly higher incidence of therapeutic success than did patients treated with UV-B alone (60.7% vs 43.3%; P<.001; number needed to treat, 5.8; 95% confidence interval [CI], 3.9-10.9). Patients who received SW UV-B or bath PUVA had a significantly higher incidence of therapeutic success than did patients treated with TW UV-B (74.9% vs 60.7%; P<.001; number needed to treat, 7.0; 95% CI, 4.6-14.9; and 78.4% vs 60.7%; P<.001; number needed to treat, 5.7; 95% CI, 4.0-9.7, respectively). Bath PUVA was not superior to SW UV-B (78.4% vs 74.9%; P = .34). CONCLUSION: Bath PUVA and SW UV-B are comparably effective treatments in psoriasis and superior to UV-B and TW UV-B.