Klinische Untersuchungen zur multimodalen Therapie des Hydrozephalus im Kleinkindesalter

Objekt: Die neurochirurgische Therapie des Hydrozephalus im Kindesalter richtet sich stark nach der Pathophysiologie der zu Grunde liegenden Erkrankung. In zwei retrospektiven Studien wurde jeweils der ventrikuloperitoneale Shunt (VPS) und die endoskopische Ventrikulozisternostomie (ETV) an unterschiedlichen Entitäten hinsichtlich verschiedener Outcomeparameter untersucht. Anhand eines multizentrischen-prospektiven Registers sollen die verschiedenen, aktuellen temporären Therapieformen mit der neuroendoskopischen Lavage (NEL) bei Kindern mit einem posthämorrhagischen Hydrozephalus (PH) verglichen werden. Methoden: Die Shunttherapie mit einem gravitationsassistierten, verstellbaren Differentialdruckventil (proGAV) und die Anwendung der ETV sind anhand von zwei Patientenkohorten der Pädiatrischen Neurochirurgie der Charité-Berlin klinisch untersucht worden. Dabei sind in der „Shunt-Studie“ 160 Patienten eingeschlossen worden, wobei die Patienten mit einer Myelomeningocele (MMC) (n=44) mit der restlichen Kohorte (Kontrollgruppe) verglichen worden sind. In der „ETV-Studie“ ist eine neuroradiologische Analyse von 21 Patienten mit einem sichtbaren Druckgradienten im 3. Ventrikel bei gleichzeitig offenen ventrikulären Abflüssen erfolgt. Der optimale Therapieansatz bei einem PH soll mit Hilfe eines prospektiven, online Registers ermittelt werden („TROPHY-Register“). Ergebnisse: Unter den 160 mit Shunt versorgten Patienten befanden sich 44 MMC Patienten, die während einer durchschnittlichen Follow-Up Zeit von 48,7±19,2 Monaten eine Shuntüberlebensrate (SSR) von 49% nach 60 Monaten zeigten (Kontrollgruppe: 39% nach 60 Monaten). Eine signifikant höhere Ventilüberlebensrate (VSR) von 69% nach 60 Monaten konnte in der Gruppe der MMC im Vergleich zur Kontrollgruppe beobachtet werden (51% nach 60 Monaten; p<0,05) („Shunt-Studie“). Die „ETV-Studie“ zeigte eine Shuntunabhängigkeit nach der ETV von 100% bei über 12 Monate alten Kindern. Alle jüngeren Kinder (n=6) mussten im Laufe des Follow-Up mit einem VPS versorgt werden. Die Ventrikelweite, gemessen mittels „frontal and occipital horn ratio“ (FOHR), zeigte einen signifikanten Rückgang direkt nach der ETV (0,5±0,08, n=19) und einen hochsignifikanten Rückgang (0,47±0,05, n=13; p<0,001) bei den Patienten, die bis zum Ende des Follow-Up keinen VPS benötigten. Um die unterschiedlichen operativen Therapiemöglichkeiten des PH zu evaluieren, ist im Rahmen des „TROPHY Register“ eine online Datenbank erstellt worden. Schlussfolgerung: Bei VPS versorgten Kindern, konnten wir geringere Revisionsraten in der Gruppe der MMC nachweisen bei nach wie vor hohen Revisionsraten, insbesondere in der Gruppe der PH. Dies unterstreicht die Bedeutung der ETV-Therapie bei einem nicht kommunizierenden Hydrozephalus und rückt die neuroradiologische Diagnostik dessen in den Vordergrund, um die richtige Indikation für die jeweilige operative Therapie stellen zu können. Zukünftige Studien sollten versuchen, die Entwicklung von Sekundärschäden zu minimieren, indem das Outcome der Therapie verbessert wird. Dies soll anhand des „TROPHY-Registers“ ermittelt werden.Objective: The neurosurgical therapy of pediatric hydrocephalus depends on its pathophysiology and requires an accurate consideration of the different interventions. In two retrospective studies, the ventriculoperitoneal shunt (VPS) and the endoscopic third ventriculocisternostomy (ETV) are evaluated on different etiologies regarding various outcome parameters. On the basis of a prospective multicenter registry, the current temporary therapy options are compared with the neuroendoscopic lavage (NEL) in infants with posthemorrhagic hydrocephalus (PH). Methods: Shunt therapy with an adjustable differential pressure valve assisted by a gravitational unit (proGAV) and the ETV were evaluated on two different patient cohorts at Pediatric Neurosurgery of Charité-Berlin. The “Shunt Study” includes 160 patients, in which the patients with a myelomeningocele (MMC) (n=44) are compared with the remaining cohort (control group). A neuroradiological analysis of 21 patients with a visible pressure gradient of the 3rdventricle but open ventricular outlets treated with an ETV was undertaken in the “ETV Study”. The beneficial therapy regimen in infants with PH shall be identified with a prospective, online registry (“TROPHY Registry”). Results: Among the 160 infants treated with a shunt, 44 MMC patients were identified, who showed a shunt survival rate (SSR) of 49% after 60 months during a mean follow–up of 48.7±19.2 months (control group: 39% after 60 months). A significant higher valve survival rate (VSR) of 69% after 60 months was observed in the MMC group in comparison to the control group (51% after 60 months; p<0.05). The “ETV Study” showed a shunt-free survival of 100% after ETV in patients older than 12 months of age. All infants younger than one year of age (n=6) received a VPS during follow-up. The ventricular width showed a significant decrease after ETV of 0.5±0.08 (n=19) and was significantly reduced at last follow–up in shunt independent patients (0.47±0.05; n=13, p<0.001). A prospective online registry is established, to enable a prospective data collection. The “TROPHY Registry” aims to evaluate the different surgical therapy options in infants with PH. Conclusion: Improved revision free survival rates in infants with MMC-related hydrocephalus were presented in comparison to other etiologies as the PH. This underlines the ETV as an important intervention in non-communicating hydrocephalus. For this reason, the radiological diagnosis of hydrocephalus plays an important role for determining the exact etiology and ensuring the optimal therapy. Future clinical studies shall target the outcome of the therapy to minimize secondary damage. The registry of the “TROPHY Study” shall enable this

Severe Traumatic Brain Injury in children—paradigm of decompressive craniectomy compared to a historic cohort

Purpose Traumatic brain injury (TBI) is one of the leading causes of death and disability in children. Medical therapy remains limited, and decompressive craniectomy (DC) is an established rescue therapy in case of elevated intracranial pressure (ICP). Much discussion deals with clinical outcome after severe TBI treated with DC, while data on the pediatric population is rare. We report our experience of treating severe TBI in two different treatment setups at the same academic institution. Methods Forty-eight patients (<= 16 years) were hospitalized with severe TBI (GCS <= 8 points) between 2008 and 2018 in a pediatric intensive care unit (ICU) at a specialized tertiary pediatric care center. Data on treatment, clinical status, and outcome was retrospectively analyzed. Outcome data included Glasgow Outcome Scale (GOS) at 3-, 12-, and 36-month follow-up. Data was compared to a historic cohort with 53 pediatric severe TBI patients treated at the same institution in a neurointensive care unit between 1996 and 2007. Ethical approval was granted (EA2/076/21). Results Between 2008 and 2018, 11 patients were treated with DC. Compared to the historic cohort, patients were younger and GCS was worse, while in-hospital mortality and clinical outcome remained similar. A trend towards more aggressive EVD placement and the internal paradigm change for treatment in a specialized pediatric ICU was observed. Conclusions In children with severe TBI treated over two decades, clinical outcome was comparable and mostly favorable in two different treatment setups. Consequent therapy is warranted to maintain the positive potential for favorable outcome in children with severe TBI

Technical Aspects and Clinical Limitations of Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

PURPOSE: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. MATERIALS AND METHODS: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. RESULTS: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). CONCLUSIONS: This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study

Background Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. Methods We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. Results Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19–1.94), wheeze (OR 1.37, 95% CI 1.16–1.63) and dyspnoea (OR 1.83, 95% CI 1.53–2.20), but not lower FVC (β=0.02 L, 95% CI −0.02–0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI −0.49–0.58%). Some findings differed by sex and gross national income. Conclusion At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.publishedVersio

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Technical aspects and clinical limitations of sperm DNA fragmentation testing in male infertility: A global survey, current guidelines, and expert recommendations

Purpose Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. Materials and Methods Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. Results The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). Conclusions This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial

Controversy and Consensus on Indications for Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations

Purpose: Sperm DNA fragmentation (SDF) testing was recently added to the sixth edition of the World Health Organization laboratory manual for the examination and processing of human semen. Many conditions and risk factors have been associated with elevated SDF; therefore, it is important to identify the population of infertile men who might benefit from this test. The purpose of this study was to investigate global practices related to indications for SDF testing, compare the relevant professional society guideline recommendations, and provide expert recommendations. Materials and Methods: Clinicians managing male infertility were invited to take part in a global online survey on SDF clinical practices. This was conducted following the CHERRIES checklist criteria. The responses were compared to professional society guideline recommendations related to SDF and the appropriate available evidence. Expert recommendations on indications for SDF testing were then formulated, and the Delphi method was used to reach consensus. Results: The survey was completed by 436 experts from 55 countries. Almost 75% of respondents test for SDF in all or some men with unexplained or idiopathic infertility, 39% order it routinely in the work-up of recurrent pregnancy loss (RPL), and 62.2% investigate SDF in smokers. While 47% of reproductive urologists test SDF to support the decision for varicocele repair surgery when conventional semen parameters are normal, significantly fewer general urologists (23%; p=0.008) do the same. Nearly 70% would assess SDF before assisted reproductive technologies (ART), either always or for certain conditions. Recurrent ART failure is a common indication for SDF testing. Very few society recommendations were found regarding SDF testing. Conclusions: This article presents the largest global survey on the indications for SDF testing in infertile men, and demonstrates diverse practices. Furthermore, it highlights the paucity of professional society guideline recommendations. Expert recommendations are proposed to help guide clinicians

Controversy and consensus on the management of elevated sperm DNA fragmentation in male infertility: A global survey, current guidelines, and expert recommendations

Purpose Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and Methods An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. Results A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4–6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians