Petra Schiller

Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke

BACKGROUND Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain. METHODS We randomly assigned 112 patients 61 years of age or older (median, 70 years; range, 61 to 82) with malignant middle-cerebral-artery infarction to either conservative treatment in the intensive care unit (the control group) or hemicraniectomy (the hemicraniectomy group); assignments were made within 48 hours after the onset of symptoms. The primary end point was survival without severe disability (defined by a score of 0 to 4 on the modified Rankin scale, which ranges from 0 [no symptoms] to 6 [death]) 6 months after randomization. RESULTS Hemicraniectomy improved the primary outcome; the proportion of patients who survived without severe disability was 38% in the hemicraniectomy group, as compared with 18% in the control group (odds ratio, 2.91; 95% confidence interval, 1.06 to 7.49; P=0.04). This difference resulted from lower mortality in the surgery group (33% vs. 70%). No patients had a modified Rankin scale score of 0 to 2 (survival with no disability or slight disability); 7% of patients in the surgery group and 3% of patients in the control group had a score of 3 (moderate disability); 32% and 15%, respectively, had a score of 4 (moderately severe disability [requirement for assistance with most bodily needs]); and 28% and 13%, respectively, had a score of 5 (severe disability). Infections were more frequent in the hemicraniectomy group, and herniation was more frequent in the control group. CONCLUSIONS Hemicraniectomy increased survival without severe disability among patients 61 years of age or older with a malignant middle-cerebral-artery infarction. The majority of survivors required assistance with most bodily needs. (Funded by the Deutsche Forschungsgemeinschaft; DESTINY II Current Controlled Trials number, ISRCTN21702227.).

DESTINY II: DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II.

Background Patients with severe space-occupying – so-called malignant – middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces mortality from about 70% to 20% without increasing the risk of being very severely disabled. Hemicraniectomy increases the chance to survive completely independent more than fivefold and doubles the chance to survive at least partly independent. Only patients up to 60-years have been included in these trials. However, patients older than 60-years represent about 50% of all patients with malignant middle cerebral artery infarcts. Data from observational studies, suggesting that older patients may not profit from hemicraniectomy, are inconclusive, because these patients have generally been treated later and less aggressively. This leads to great uncertainty in everyday clinical practice. Aims To investigate the efficacy of early hemicraniectomy in patients older than 60-years with malignant MCA infarcts. Materials & Methods DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II is a randomised controlled trial including patients 61-years and older with malignant middle cerebral artery infarcts. Patients are randomised to either maximum conservative treatment alone or in addition to early hemicraniectomy within 48 h after symptom onset. The trial uses a sequential design with a maximum number of 160 patients to be enrolled (ISRCTN 21702227). Discussion In the face of an ageing population, the potential benefit of hemicraniectomy in older patients is of major clinical relevance, but remains controversial. Conclusion The results of this trial are expected to directly influence decision making in these patients.

Stroke-Related Early Tracheostomy Versus Prolonged Orotracheal Intubation in Neurocritical Care Trial (SETPOINT): A Randomized Pilot Trial.

Background and Purpose— Optimal timing of tracheostomy in ventilated patients with severe stroke is unclear. We aimed to investigate feasibility, safety, and potential advantages of early tracheostomy in these intensive care unit (ICU) patients. Methods— This prospective, randomized, parallel-group, controlled, open, and outcome-masked pilot trial was conducted in neurological/neurosurgical ICUs of a university hospital. Patients with severe ischemic or hemorrhagic stroke and an estimated need for at least 2 weeks of ventilation were randomized to either early tracheostomy (within day 1–3 from intubation; early) or to standard tracheostomy (between day 7–14 from intubation if extubation could not be achieved or was not feasible; standard). The primary outcome was length of stay in the ICU; secondary outcomes were diverse aspects of the ICU course. Results— Sixty patients were randomized and analyzed. No differences were observed with regard to the primary outcome length of stay in the ICU (median 18 [interquartile range 16–28] versus 17 [interquartile range 13–22] days, median difference: 1 [−2 to 6]; P=0.38) or to most secondary outcomes, including adverse effects. Instead, use of sedatives (62% versus 42% of ICU stay, median difference 17.5 [3.3–29.2]; P=0.02), ICU mortality (ICU deaths 3 [10%] versus 14 [47%]; P<0.01) and 6-month mortality (deaths 8 [27%] versus 18 [60%]; P=0.02) were lower in the early group than in the standard group, respectively. Conclusions— Early tracheostomy in ventilated intensive care stroke patients is feasible, and safe, and presumably reduces sedation need. Whether the suggested benefits in mortality and outcome truly exist has to be determined by a larger multicenter trial. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT01261091.

Quality of reporting of clinical non-inferiority and equivalence randomised trials - update and extension

BackgroundNon-inferiority and equivalence trials require tailored methodology and therefore adequate conduct and reporting is an ambitious task. The aim of our review was to assess whether the criteria recommended by the CONSORT extension were followed.MethodsWe searched the Medline database and the Cochrane Central Register for reports of randomised non-inferiority and equivalence trials published in English language. We excluded reports on bioequivalence studies, reports targeting on other than the main results of a trial, and articles of which the full-text version was not available. In total, we identified 209 reports (167 non-inferiority, 42 equivalence trials) and assessed the reporting and methodological quality using abstracted items of the CONSORT extension.ResultsHalf of the articles did not report on the method of randomisation and only a third of the trials were reported to use blinding. The non-inferiority or equivalence margin was defined in most reports (94%), but was justified only for a quarter of the trials. Sample size calculation was reported for a proportion of 90%, but the margin was taken into account in only 78% of the trials reported. Both intention-to-treat and per-protocol analysis were presented in less than half of the reports. When reporting the results, a confidence interval was given for 85% trials. A proportion of 21% of the reports presented a conclusion that was wrong or incomprehensible. Overall, we found a substantial lack of quality in reporting and conduct. The need to improve also applied to aspects generally recommended for randomised trials. The quality was partly better in high-impact journals as compared to others.ConclusionsThere are still important deficiencies in the reporting on the methodological approach as well as on results and interpretation even in high-impact journals. It seems to take more than guidelines to improve conduct and reporting of non-inferiority and equivalence trials.

Benefits of early tracheostomy in ventilated stroke patients? Current evidence and study protocol of the randomized pilot trial SETPOINT (Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial)

Rationale Ventilated intensive care patients with ischemic or hemorrhagic strokes have a poor prognosis. Early tracheostomy has led to advantages in selected groups of non-cerebrovascular intensive care patients, including shorter ventilation time, shorter intensive care unit length of stay, and reduced complications. It is completely unclear whether ventilated stroke patients might benefit from early tracheostomy, too. Aim Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial (SETPOINT) is a pilot trial aiming to investigate the safety, feasibility, and potential benefits of early tracheostomy vs. prolonged intubation (and possibly late tracheostomy) in patients with severe ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The primary objective is to compare early tracheostomy and prolonged intubation with respect to the intensive care unit – length of stay and the time until the start of rehabilitation in these patients. Design SETPOINT is a prospective, randomized, controlled, outcome observer-blinded, monocenter trial. Patients with severe ischemic stroke, intracerebral or subarachnoid hemorrhage requiring intubation and ventilation are eligible. After passing predefined criteria, enrolled patients are randomized to either percutaneous tracheostomy within the first three-days from intubation or to weaning/extubation attempts or percutaneous tracheostomy between days 7 and 14 from intubation (n = 30 per group). Study outcomes The primary end-point is the intensive care unit length of stay. Secondary end-points are functional outcome and mortality at discharge and after six-months, duration to transferability, duration of ventilation, duration and quality of weaning from respirator, need of analgesia and sedation, procedure-related complications, frequency of pneumonia and sepsis, and costs of treatment. Discussion To clarify the potential benefit of early tracheostomy in critical care ventilated stroke patients, a randomized multicenter trial in a larger patient population is clearly needed. If this monocentric pilot gives promising safety, feasibility, and benefit results, such a multicenter trial will be planned. The results will have a relevant direct impact on the critical care of stroke.

Recontouring teeth and closing diastemas with direct composite buildups: A 5-year follow-up

OBJECTIVES Adhesive resin composite technology enables dentists to add composite material to tooth surfaces to close gaps and reshape tooth form without cavity preparation. This option creates new possibilities for minimally invasive dentistry as the tooth shape, position and colour can be altered without loss of tooth substance. However, evidence-based data on direct composite buildups are rare. METHODS The purpose of this study was to evaluate the outcome and to document the occurrence of unfavourable events and clinical findings of 176 direct composite buildups that had been performed in the Department of Conservative Dentistry, University Hospital Heidelberg, Germany, between 2002 and 2008. Outcome was categorised as failure (F), survival (SR) or success (S). Restorations still in place and without prior failure at follow-up were qualitatively rated using modified USPHS/FDI criteria. RESULTS During the follow-up period, 30 restorations were found to have had unfavourable events or clinical findings. All restorations were repaired, and they remained in situ (SR). No complete loss (F) was recorded. The overall survival rate was 84.6% after 60 months (95%, confidence interval [CI]: 78.5 and 90.6). Clinical quality was rated excellent or good for most (>90%) of the restorations examined. CONCLUSIONS The direct composite buildups observed in this study were found to have promising clinical outcome and good quality parameters after 5 years. If a noninvasive or minimally invasive treatment approach is indicated, direct composite buildups provide an acceptable treatment alternative for the aesthetic correction and reshaping of anterior teeth. CLINICAL SIGNIFICANCE The application of direct composite buildups in clinical cases in which a non- or minimally invasive treatment approach is indicated provides an excellent treatment alternative for gold-standard treatment options like laboratory-made crowns and porcelain veneers. Restorations in the present investigation showed a functional survival rate of 100%, an overall survival rate of 84.6% after 5 years.

DeloRes trial: study protocol for a randomized trial comparing two standardized surgical approaches in rectal prolapse - Delorme’s procedure versus resection rectopexy

BackgroundMore than 100 surgical approaches to treat rectal prolapse have been described. These can be done through the perineum or transabdominally. Delorme’s procedure is the most frequently used perineal, resection rectopexy the most commonly used abdominal procedure. Recurrences seem more common after perineal compared to abdominal techniques, but the latter may carry a higher risk of peri- and postoperative morbidity and mortality.Methods/DesignDeloRes is a randomized, controlled, observer-blinded multicenter trial with two parallel groups. Patients with a full-thickness rectal prolapse (third degree prolapse), considered eligible for both operative methods are included. The primary outcome is time to recurrence of full-thickness rectal prolapse during the 24 months following primary surgery. Secondary endpoints are time to and incidence of recurrence of full-thickness rectal prolapse during the 5-year follow-up, duration of surgery, morbidity, hospital stay, quality of life, constipation, and fecal incontinence. A meta-analysis was done on the basis of the available data on recurrence rates from 17 publications comprising 1,140 patients. Based on the results of a meta-analysis it is assumed that the recurrence rate after 2 years is 20% for Delorme’s procedure and 5% for resection rectopexy. Considering a rate of lost to follow-up without recurrence of 30% a total of 130 patients (2 x 65 patients) was calculated as an adequate sample size to assure a power of 80% for the confirmatory analysis.DiscussionThe DeloRes Trial will clarify which procedure results in a smaller recurrence rate but also give information on how morbidity and functional results compare.Trial registrationGerman Clinical Trial Number DRKS00000482

Fiber-reinforced composite fixed dental prostheses in the anterior area: A 4.5-year follow-up

STATEMENT OF PROBLEM Currently, fiber-reinforced fixed dental prostheses (FRC FDPs) are a reliable treatment option for the restoration of single missing teeth in the anterior area. PURPOSE The purpose of this study was to evaluate the survival of direct and semidirect fabricated FRC FDPs in the anterior area and to rate the quality of the outcome. MATERIAL AND METHODS Twenty-four participants (12 men, 12 women) were included in the investigation. The prostheses were made of preimpregnated, unidirectional fiber-reinforced composite (FRC) (everStick, GC) by using a direct (n=18) or semidirect (n=6) technique. Eleven FRC FDPs had been placed in the maxilla and 13 had been placed in the mandible. Follow-up intervals were recorded, and the prostheses were classified as success (successful), survival (unfavorable event but still in vivo), or failure (lost). Quality was rated according to the modified United States Public Health Services (USPHS) or Ryge criteria. RESULTS The FRC FDPs evaluated in this study showed an overall survival rate (success) of 72.6% and a functional survival rate (success + survival) of 85.6% (median follow-up 54 months). According to the USPHS/Ryge criteria, most of the restorations displayed excellent or good quality. Survival analysis was performed by the Kaplan-Meier method. CONCLUSIONS The FRC FDPs evaluated in this study showed promising survival rates and good quality after a median follow-up period of 4.5 years (quartile range 3.5 to 6.3 years), thus indicating that FRC FDPs are reliable treatment options for the restoration of single missing teeth in the anterior area. The use of preimpregnated FRC materials with higher fiber content might improve the clinical fabrication of FRC FDPs but does not influence their long-term clinical survival.

Extracellular vesicles mediate intercellular communication: Transfer of functionally active microRNAs by microvesicles into phagocytes

Cell activation and apoptosis lead to the formation of extracellular vesicles (EVs) such as exosomes or microvesicles (MVs). EVs have been shown to modulate immune responses; recently, MVs were described to carry microRNA (miRNA) and a role for MVs in the pathogenesis of autoimmune diseases has been discussed. Here we systematically characterized MVs and exosomes according to their release stimuli. The miRNA content of viable or apoptotic human T lymphocytes and the corresponding MVs was analyzed. miRNA, protein and surface marker expression, as well as cytokine release by human monocytes was measured after EV engulfment. Finally, miRNA expression in T lymphocytes and MVs of healthy individuals was compared with those of systemic lupus erythematosus (SLE) patients. We demonstrate that, depending on the stimuli, distinct subtypes of EVs are released, differing in size and carrying a specific RNA profile. We observed an accumulation of distinct miRNAs in MVs after induction of apoptosis and the transfer of functional miRNA by MVs into human monocytes. MVs released from apoptotic cells provoke less of an inflammatory response than those released from viable cells. MiR‐155*, miR‐34b and miR‐34a levels in T lymphocytes and corresponding MVs were deregulated in SLE when compared to healthy individuals.

Extracellular vesicle subtypes released from activated or apoptotic T-lymphocytes carry a specific and stimulus-dependent protein cargo

Extracellular vesicles (EVs) are released from nearly all mammalian cells and different EV populations have been described. Microvesicles represent large EVs (LEVs) released from the cellular surface, while exosomes are small EVs (SEVs) released from an intracellular compartment. As it is likely that different stimuli promote the release of distinct EV populations, we analyzed EVs from human lymphocytes considering the respective release stimuli (activation Vs. apoptosis induction). We could clearly separate two EV populations, namely SEVs (average diameter <200 nm) and LEVs (diameter range between 200 and 1000 nm). Morphology and size were analyzed by electron microscopy and nanoparticle tracking analysis. Apoptosis induction caused a massive release of LEVs, while activated T-cells released SEVs and LEVs in considerably lower amounts. The release of SEVs from apoptotic T-cells was comparable with LEV release from activated ones. LEVs contained signaling proteins and proteins of the actin-myosin cytoskeleton. SEVs carried cytoplasmic/endosomal proteins like the 70-kDa heat shock protein 70 (HSP70) or tumor susceptibility 101 (TSG101), microtubule-associated proteins, and ubiquitinated proteins. The protein expression profile of SEVs and LEVs changed substantially after the induction of apoptosis. After apoptosis induction, HSP70 and TSG101 (often used as exosome markers) were highly expressed within LEVs. Interestingly, in contrast to HSP70 and TSG101, gelsolin and eps15 homology domain-containing protein 3 (EHD3) turned out to be specific for SEVs irrespective of the stimulus causing the EV release. Finally, we detected several subunits of the proteasome (PSMB9, PSMB10) as well as the danger signal HMGB1 exclusively within apoptotic cell-released LEVs. Thus, we were able to identify new marker proteins that can be useful to discriminate between distinct LEV subpopulations. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD009074.