Demonstrating the reliability of in vivo metabolomics based chemical grouping: towards best practice.

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.

[Diagnosis and Treatment in frontobasal fractures]. / Vorgehen bei frontobasalen Frakturen.

Traumatic brain injury can result in frontobasal fractures (FBF). The goals of treatment for FBF are to eliminate primary morbidity and/or prevent secondary morbidity. Of particular importance in this regard is the proximity of important sensory organs for hearing, vision, smell, and taste, as well as their supplying nervous structures. Medical history, clinical findings, or CT scan are necessary and should lead to an individual evaluation. Depending on the severity of the fractures, the following disciplines may be involved in the treatment of FBF: neurosurgery, plastic surgery, oral and maxillofacial surgery, and/or otorhinolaryngology. Particularly less invasive endoscopic endonasal therapy is a specialty of otorhinolaryngologic surgeons and has not been widely established in other disciplines. The present work provides an overview of the current state of the art in terms of the following aspects, taking into account the current literature: anatomic principles, classification of fractures, diagnostics (in particular clinical examination, imaging, and laboratory chemistry tests), clinical symptoms, and treatment.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

Exploring the most visible websites on cutaneous T-cell lymphoma-revealing limited quality of patient health information on the internet.

BACKGROUND: Patients diagnosed with cancer frequently search the Internet for health information. Yet, the quality of CTCL online information has not been investigated so far. OBJECTIVES: The aim of this study was to identify and assess the most visible websites on CTCL. METHODS: An Internet search on the top three search engines Google, Yahoo and Bing was performed for the terms 'cutaneous T-cell-lymphoma', 'mycosis fungoides' and 'Sézary syndrome'. After selecting the most frequented websites suitable for patients' information, we investigated content quality, readability and popularity. Eighty-nine websites were evaluated for HONcode quality certification, social media popularity, Alexa popularity rank, topicality and readability levels. Furthermore, the websites' content on 13 major topics according to guidelines on CTCL was assessed. RESULTS: Twenty-three (25.8%) websites were HONcode certified. Evaluated websites were difficult to read requiring at least 9 years of US school education to properly understand the information. More than half of all websites (57.3%) have not been updated for three or more years (or did not contain any update information). We found greatly varying quality and popularity of online patient information. Out of 1157 topics (equivalent to 13 different topics on 89 websites), 59.44% were mentioned on the websites. Of these, 40% contained incorrect or incomplete information. Publicly provided websites presented the different topics more thoroughly. We could further show that HONcode certified websites received better quality and readability scores. CONCLUSIONS: We found major shortcomings regarding readability, completeness and reliability of websites on CTCL. Nevertheless, highly selected websites on CTCL can serve as a valuable and reliable source of patient information. As a consequence, oncologists have an obligation to be aware of and guide their patients to available websites that contain reliable and appropriate information.

Effectiveness of the lateral pedicled endonasal flap for prevention of restenosis in frontal sinus drillouts.

BACKGROUND: Frontal sinus median drainage according to Draf is an established procedure for achieving maximum drainage of the frontal sinus. Despite great efforts and several modifications, restenosis of the neo-ostium is still a persistent problem. This study presents an approach by implementing local mucosal flaps to prevent restenosis and compares it with the conventional technique without using the flap. METHODS: Description of endonasal, lateral pedicle mucosal flap. A Draf III procedure was performed on 156 patients between 2012 and 2021. Data for 123 of the included patients were retrospectively analyzed in terms of surgical indication, technique, postoperative aftercare and patency of the drainage pathway. The follow-up observation period was between 3 and 24 months. RESULTS: Treatment with the pedicle mucosal flap took place in 86 cases. 37 patients were treated as a control group without this flap. The analysis showed a significant association to the event "total closure of the drainage pathway" for surgical technique, as well as in the case of the presence of an allergy and the existence of Samter's triad. Furthermore, there was a significant association between the onset of "near total closure of the frontal sinus ostium" and Samter';s triad, CRS and revision surgery was involved. CONCLUSIONS: Use of an endonasal lateral pedicle flap for reconstruction of mucosal defects in frontal sinus surgery improves the long-term chances of a patent drainage pathway. Bone exposed by drilling was covered with a local mucosal flap for a faster epithelialization, healing and less scarring.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

Stroke care during the COVID-19 pandemic: experience from three large European countries.

In order to cope with the exponentially increasing number of patients infected with SARS-CoV-2, European countries made enormous efforts to reorganize medical assistance and several diseases, including stroke, were particularly impacted. We report the experience of stroke neurologists from three European countries (Italy, France and Germany) that faced the pandemic at diverse time points and with different approaches, depending on their resources and healthcare system organization. Pre-hospital and in-hospital acute stroke pathways were reorganized to prioritize COVID-19 management and, in severely affected regions of Italy and France, stroke care was centralized to a limited number of centers, whereas the remaining stroke units were dedicated to patients with COVID-19. Access to acute stroke diagnostics and time-dependent therapies was limited or delayed because of reduced capacities of emergency services due to the burden of patients with COVID-19. A marked reduction in the number of patients presenting with transient ischaemic attack and stroke was noted in the emergency departments of all three countries. Although we only have preliminary data, these conditions may have affected stroke outcome. These indirect effects of the COVID-19 pandemic could negate the efforts of stroke neurologists over the last few years to improve outcome and reduce mortality of stroke patients. Although the SARS-CoV-2 infection rate is slowing down in Europe, the effects of ending lockdown in the next months are unpredictable. It is important for the European and world stroke community to share what has been learned so far to be plan strategies to ensure stroke care in the future and upcoming challenging times.

[Nationwide treatment reality of patients with acute ischemic stroke in Germany : Update of the regionalized analysis on use of recanalization treatment procedures and stroke complex treatment]. / Bundesweite Versorgungsrealität von Patienten mit akutem Hirninfarkt in Deutschland : Update der regionalisierten Analyse zur Anwendung rekanalisierender Therapieverfahren und einer Schlaganfallkomplexbehandlung.

BACKGROUND: The guidelines of the German Society for Neurology regarding the diagnostics and treatment of acute ischemic stroke contain the general recommendation of treatment on a stroke unit (SU) and the use of recanalizing treatment (intravenous thrombolysis, IVT; mechanical thrombectomy, MT) in appropriate patients. The nationwide availability of all three components represents a large organizational and healthcare political challenge. OBJECTIVE: Updated nationwide analysis of treatment rates in Germany based on a regionalized evaluation. METHODS: Based on the patient's place of residence, nationwide data of all hospitalized patients were evaluated using the German diagnosis-related groups (DRG) statistics from 2018 and compared with previous years. The rates for SU treatment, IVT and MT in the 412 German regional districts were analyzed. The 412 regions were grouped according to the degree of urbanization. RESULTS: Nationwide, a total of 224,647 patient cases with a main diagnosis of acute ischemic stroke were treated in 1382 hospitals in Germany in 2018. Overall, relatively high treatment rates were determined (SU = 73.3%; IVT = 16.4%; MT = 6.5%). Only 10.2% of treatments in the SU were performed on a SU located at a hospital with no neurology department. The regionalized analysis showed large treatment ranges for all three therapeutic components, with significantly lower treatment rates in regions with a lower degree of urbanization (SU, IVT, MT rates: urban = 75.4%, 17.4%, 7.5% and rural = 67.1%; 15.4%, 5.3%, respectively). CONCLUSION: Hospitalized healthcare in Germany shows high treatment rates for both SU admission and acute recanalization treatment in patients with acute ischemic stroke; however, there is further optimization potential in rural regions.

[Comparability of different data sources on stroke care in Germany]. / Vergleichbarkeit unterschiedlicher Datenquellen zur Schlaganfallversorgung in Deutschland.

This article reviews different methodological approaches for determining treatment reality of ischemic stroke patients in acute care hospitals. Considering specific advantages and disadvantages of two different epidemiologic approaches, a specific comparison was carried out of cases from a structured analysis of the nationwide German diagnosis-related groups (DRG) statistics and data from the acute stroke treatment in Hesse (SA_HE) for 2018 collated by the office for quality management. According to the DRG statistics and the SA_HE data, 16,267 and 15,643 acute ischemic stroke patients (ICD code I63) were treated in Hesse in 2018, with 53.7% and 54.5% males, respectively. The overall age distribution did not show significant differences between the two data sources; however, stroke patients over the age of 70 years were registered significantly more often in the DRG statistics. The rates of systemic thrombolysis were 16.5% in both data sources and the rates of mechanical thrombectomy were 5.6% and 5.9%, respectively. The analysis shows that after a rational limitation of the included cases and based on the place of treatment, there were no statistically significant differences concerning the number of hospitalized patients with ischemic stroke, distribution of gender and age as well as the documented rates of systemic thrombolysis and mechanical thrombectomy. It can therefore be concluded that the well-controlled stroke quality register examined is able to capture a sufficient number of hospitalized acute ischemic stroke cases and treatment rates. Therefore, it appears to be recommendable to adopt the strict Hessian guidelines for data acquisition and control nationwide. In this way a nationwide combined analysis of data from the working group of German stroke registers and the DRG statistics would be possible.

[Unilateral diseases of the maxillary sinus]. / Einseitige Erkrankungen der Kieferhöhle.

Unilateral diseases of the maxillary sinus are among the most common rhinologic diagnoses. The diversity of these diseases can represent a challenge for the treating physician. The spectrum ranges from harmless maxillary sinus cysts that seldom require treatment, to highly aggressive malignant tumors. Special attention should be given to the management of inverted papilloma. These benign tumors are characterized by high recurrence rates and the potential for malignant transformation. The key to minimizing recurrence is precise surgical intervention. Other unilateral maxillary sinus diseases such as the antrochoanal polyp and the fungus ball (aspergilloma) are also discussed in depth.

[Rare diseases of the maxillary sinus]. / Seltene Erkrankungen der Kieferhöhle.

BACKGROUND: Silent sinus syndrome (SSS), organized hematoma (OH), and pneumosinus dilatans (PD) are rare, usually unilateral diseases of the maxillary sinus. Due to misinterpretation, excessive diagnostics and unnecessarily aggressive surgery or a delay in diagnostics and treatment are common. OBJECTIVE: The objective of this study was to develop reasonable and comprehensible diagnostic criteria to improve diagnosis and treatment of these rare diseases. METHODS: In this retrospective study, all patients treated for SSS, OH, and PD from 2012 to 2019 were identified. Patient history, diagnostic tests and results, and postoperative course were analyzed and compared with the available literature. RESULTS: During the study period, 7 patients with SSS, 3 patients with PD, and 2 patients with OH were treated and available for follow-up. Comparison of these patients with the literature allowed us to develop diagnostic criteria. CONCLUSION: Medical history combined with endoscopic and radiologic criteria should improve preoperative diagnosis of these three rare diseases of the maxillary sinus and help to distinguish them from other differential diagnoses. This approach should minimize morbidity for the patients.

[Autopneumonectomie. A Forgotten Disease]. / Autopneumonektomie. Ein vergessenes Krankheitsbild.

HISTORY: An 80-year old female was referred to our hospital with left internal carotid artery stenosis and a childhood history of hemoptysis. INVESTIGATIONS AND DIAGNOSIS: The ECG showed 2nd degree Mobitz atrio-ventricular block. The chest x-ray and computerized tomography identified a shift of the mediastinum and the heart to the left. The left lung was completely destroyed whilst the right lung was enlarged and crossed the midline. Pulmonary function tests revealed a moderate restrictive ventilation disorder. The diagnosis of autopneumonectomy was based on patient history together with radiological findings. TREATMENT AND COURSE: A pacemaker was implanted with two stimulation electrodes via a left cephalic venous cutdown. A carotid endarterectomy was also performed without any complication. CONCLUSION: After autopneumonectomy, postpneumonectomy like syndrome may occur in very rare cases, whereupon operative treatment is mandatory. Any respiratory infections should be treated with antibiotics. Pacemaker electrode placement via the subclavian vein is contraindicated due to the risk of a catastrophic pneumothorax.

Why do sub-Saharan Africans present late for HIV care in Switzerland?

OBJECTIVES: Late presentation (LP) to HIV care disproportionally affects individuals from sub-Saharan Africa (SSA). We explored the reasons for late presentation to care among this group of patients in the Swiss HIV Cohort Study. METHODS: The prevalence of LP was compared between patients from Western Europe (WE) and those from SSA enrolled between 2009 and 2012. Patients were asked about HIV testing, including access to testing and reasons for deferring it, during face-to-face interviews. RESULTS: The proportion of LP was 45.8% (435/950) among patients from WE, and 64.6% (126/195) among those from SSA (P < 0.001). Women from WE were slightly more likely to present late than men (52.6% versus 44.5%, respectively; P = 0.06), whereas there was no sex difference in patients from SSA (65.6% versus 63.2%, respectively; P = 0.73). Compared with late presenters from WE, those from SSA were more likely to be diagnosed during pregnancy (9.1% versus 0%, respectively; P < 0.001), but less likely to be tested by general practitioners (25.0% versus 44.6%, respectively; P = 0.001). Late presenters from SSA more frequently reported 'not knowing about anonymous testing possibilities' (46.4% versus 27.3%, respectively; P = 0.04) and 'fear about negative reaction in relatives' (39.3% versus 21.7%, respectively; P = 0.05) as reasons for late testing. Fear of being expelled from Switzerland was reported by 26.1% of late presenters from SSA. CONCLUSIONS: The majority of patients from SSA were late presenters, independent of sex or education level. Difficulties in accessing testing facilities, lack of knowledge about HIV testing and fear-related issues are important drivers for LP in this population.

Thrombectomy in posterior circulation stroke: differences in procedures and outcome compared to anterior circulation stroke in the prospective multicentre REVASK registry.

BACKGROUND AND PURPOSE: In contrast to anterior circulation stroke (ACS), there is no evidence from randomized trials that mechanical thrombectomy (MT) with modern stent retrievers or thromboaspiration is safe and effective in posterior circulation stroke (PCS). METHODS: The present analysis was based on the prospective multicentre Registry on Revascularization in Ischemic Stroke Patients (REVASK) in Germany. Demographic data, periprocedural times and complications, recanalization rates, and functional outcome at discharge and after 3 months were compared between 139 consecutive patients with PCS (84.9% basilar artery, 16.5% vertebral artery and 4.3% posterior cerebral artery occlusion) and 961 patients with ACS treated with MT. RESULTS: Compared to ACS, PCS patients were significantly younger (65 vs. 69 years, P = 0.021) and had a lower median National Institutes of Health Stroke Scale (NIHSS) score at baseline (12 vs. 15, P = 0.024). Patients with PCS had a significantly longer time delay between symptom onset and both start and end of the MT procedure. Successful recanalization and thrombectomy passes did not significantly differ between the two groups. No symptomatic intracranial haemorrhage occurred in PCS compared to 3% in ACS (P = 0.010). The median NIHSS score at discharge was 3 in PCS and 4 in ACS. Favourable functional outcome at 3 months (modified Rankin Scale 0-2 38.0% vs. 42.6%, P = 0.392) and mortality (33.7% vs. 30.8%, P = 0.539) did not differ significantly between PCS and ACS. CONCLUSIONS: The study suggests that MT in PCS shows a lower risk of symptomatic intracranial haemorrhage and similar effectiveness compared to ACS. PCS patients also seem to benefit from MT started beyond 6 h after symptom onset.

Anthropogenic control over wintertime oxidation of atmospheric pollutants.

During winter in the mid-latitudes, photochemical oxidation is significantly slower than in summer and the main radical oxidants driving formation of secondary pollutants, such as fine particulate matter and ozone, remain uncertain, owing to a lack of observations in this season. Using airborne observations, we quantify the contribution of various oxidants on a regional basis during winter, enabling improved chemical descriptions of wintertime air pollution transformations. We show that 25-60% of NOx is converted to N2O5 via multiphase reactions between gas-phase nitrogen oxide reservoirs and aerosol particles, with ~93% reacting in the marine boundary layer to form >2.5 ppbv ClNO2. This results in >70% of the oxidizing capacity of polluted air during winter being controlled, not by typical photochemical reactions, but from these multiphase reactions and emissions of volatile organic compounds, such as HCHO, highlighting the control local anthropogenic emissions have on the oxidizing capacity of the polluted wintertime atmosphere.

Cellular and Acellular Assays for Measuring Oxidative Stress Induced by Ambient and Laboratory-Generated Aerosols.

INTRODUCTION: Many studies have established associations between exposure to air pollution, or atmospheric particulate matter (PM), and adverse health effects. An increasing array of studies have suggested oxidative stress as a possible mechanism by which PM-induced health effects arise, and as a result, many chemical and cellular assays have been developed to study PM-induced oxidant production. Although significant progress has been made in recent years, there are still many gaps in this area of research that have not been addressed. Many prior studies have focused on the aerosol of primary origin (e.g., the aerosol emitted from combustion engines) although the aerosol formed from the oxidation of volatile species, secondary organic aerosol (SOA), has been shown to be the predominant type of aerosol even in urban areas. Current SOA health studies are limited in number, and as such, the health effects of SOA are poorly characterized. Also, there is a lack of perspective in terms of the relative toxicities of different SOA systems. Additionally, although chemical assays have identified some SOA constituents associated with adverse health endpoints, the applicability of these results to cellular responses has not been well established. SPECIFIC AIMS: The overall objective of this study was to better understand the oxidative properties of different types and components of PM mixtures (especially SOA) through systematic laboratory chamber experiments and ambient field studies. The study had four specific aims.1 To develop a cellular assay optimized for measuring reactive oxygen and nitrogen species (ROS/RNS) production resulting from PM exposure and to identify a robust parameter that could represent ROS/RNS levels for comparison with different endpoints.2 To identify ambient PM components associated with ROS/RNS production and evaluate whether results from chemical assays represented cellular responses in terms of ROS/RNS production.3 To investigate and provide perspective on the relative toxicities of SOA formed from common biogenic and anthropogenic precursors under different conditions (e.g., humidity, nitrogen oxides [NOx], and redox-active metals) and identify bulk aerosol properties associated with cellular responses.4 To investigate the effects of photochemical aging on aerosol toxicity. METHODS: Ambient PM samples were collected from urban and rural sites in the greater Atlanta area as part of the Southeastern Center for Air Pollution and Epidemiology (SCAPE) study between June 2012 and October 2013. The concentrations of water-soluble species (e.g., water-soluble organic carbon [WSOC], brown carbon [Br C], and metals) were characterized using a variety of instruments. Samples for this study were chosen to span the observed range of dithiothreitol (DTT) activities.Laboratory studies were conducted in the Georgia Tech Environmental Chamber (GTEC) facility in order to generate SOA under well-controlled photooxidation conditions. Precursors of biogenic origin (isoprene, α-pinene, and ß-caryophyllene) and anthropogenic origin (pentadecane, m-xylene, and naphthalene) were oxidized under various formation conditions (dry vs. humid, NOx, and ammonium sulfate vs. iron sulfate seed particles) to produce SOA of differing chemical composition and mass loading. For the naphthalene system, a series of experiments were conducted with different initial hydrocarbon concentrations to produce aerosols with various degree of oxidation. A suite of instruments was utilized to monitor gas- and particle-phase species. Bulk aerosol properties (e.g., O:C, H:C, and N:C ratios) were measured using a high-resolution time-of-flight aerosol mass spectrometer. Filter samples were collected for chemical oxidative potential and cellular measurements. For the naphthalene system, multiple filter samples were collected over the course of a single experiment to collect aerosols of different photochemical aging.For all filter samples, chemical oxidative potentials were determined for water-soluble extracts using a semiautomated DTT assay system. Murine alveolar macrophages and neonatal rat ventricular myocytes were also exposed to PM samples extracted in cell culture medium to investigate cellular responses. ROS/RNS production was detected using the intracellular ROS/RNS probe, carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFA), whereas cellular metabolic activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Finally, cytokine production, that is, secreted levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were measured post-exposure using an enzyme-linked immunosorbent assay (ELISA). To identify PM constituents associated with oxidative properties, linear regressions between oxidative properties (cellular responses or DTT activity) and aerosol composition (metals, elemental ratios, etc.) were evaluated using Pearson's correlation coefficient, where the significance was determined using multiple imputation and evaluated using a 95% confidence interval. RESULTS: We optimized several parameters for the ROS/RNS assay, including cell density (2 × 104 cells/well for macrophages and 3.33 × 104 cells/well for cardiomyocytes), probe concentration (10 µM), and sample incubation time (24 hours). Results from both ambient and laboratory-generated aerosols demonstrate that ROS/RNS production was highly dose-dependent and nonlinear with respect to PM dose. Of the dose-response metrics investigated in this study (maximum response, dose at which the response is 10% above the baseline [threshold], dose at which 50% of the response is attained [EC50], rate at which the maximum response is attained [Hill slope], and area under the dose-response curve [AUC]), we found that the AUC was the most robust parameter whose informativeness did not depend on dose range.A positive, significant correlation was observed between ROS/RNS production as represented by AUC and chemical oxidative potential as measured by DTT for ambient samples collected in summer. Conversely, a relatively constant AUC was observed for ambient samples collected in winter regardless of the corresponding DTT activity. We also identified several PM constituents (WSOC, BrC, iron, and titanium) that were significantly correlated with AUC for summer samples. The strong correlation between organic species and ROS/RNS production highlights a need to understand the contribution of organic aerosols to PM-induced health effects. No significant correlations were observed for other ROS/RNS metrics or PM constituents, and no spatial trends were observed.For laboratory-generated aerosol, precursor identity influenced oxidative potentials significantly, with isoprene and naphthalene SOA having the lowest and highest DTT activities, respectively. Both precursor identity and formation condition significantly influenced inflammatory responses induced by SOA exposure, and several response patterns were identified for SOA precursors whose photooxidation products share similar carbon-chain length and functionalities. The presence of iron sulfate seed particles did not have an apparent effect on oxidative potentials; however, a higher level of ROS/RNS production was observed for all SOA formed in the presence of iron sulfate compared with ammonium sulfate. We also identified a significant positive correlation between ROS/RNS production and average carbon oxidation state, a bulk aerosol property. It may therefore be possible to roughly estimate ROS/RNS production using this property, which is readily obtainable. This correlation may have significant implications as aerosols have an atmospheric lifetime of a week, during which average carbon oxidation state increases because of atmospheric photochemical aging. Our results suggest that aerosols might become more toxic as they age in the atmosphere. Finally, in the context of ambient samples, laboratory-generated SOA induced comparable or higher levels of ROS/RNS. Oxidative potentials for all laboratory SOA systems, with the exception of naphthalene (which was higher), were all comparable with oxidative potentials observed in ambient samples.

[Anteromedial maxillectomy for improvement of nasal breathing : Advanced procedure in surgery of the lateral nasal wall]. / Anteriomediale Maxillektomie zur Verbesserung der Nasenatmung : Erweiterte Verfahren in der Chirurgie der lateralen Nasenwand.

The aim of classical surgical correction for nasal breathing impairment is to harmonically extend the physiological space in the nose by an operation of the nasal septum and inferior nasal turbinate. In this way the airflow character should be maintained and the mucosa protected in order not to endanger the respiratory function of the nose. This article presents an operative approach developed stepwise a few years ago in which the different operative steps are carried out depending on the individual anatomical situation and the underlying mucosal disease. The focus is on partial anteromedial maxillectomy.

Association between exposure to antiretroviral drugs and the incidence of hypertension in HIV-positive persons: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study.

OBJECTIVES: Previous studies have suggested that hypertension in HIV-positive individuals is associated primarily with traditional risk factors such as older age, diabetes and dyslipidaemia. However, controversy remains as to whether exposure to antiretroviral (ARV) drugs poses additional risk, and we investigated this question in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort. METHODS: The incidence of hypertension [systolic blood pressure (BP) > 140 and/or diastolic BP > 90 mmHg and/or initiation of antihypertensive treatment] was determined overall and in strata defined by demographic, metabolic and HIV-related factors, including cumulative exposure to each individual ARV drug. Predictors of hypertension were identified using uni- and multivariable Poisson regression models. RESULTS: Of 33 278 included persons, 7636 (22.9%) developed hypertension over 223 149 person-years (PY) [incidence rate: 3.42 (95% confidence interval (CI) 3.35-3.50) per 100 PY]. In univariable analyses, cumulative exposure to most ARV drugs was associated with an increased risk of hypertension. After adjustment for demographic, metabolic and HIV-related factors, only associations for nevirapine [rate ratio 1.07 (95% CI: 1.04-1.13) per 5 years] and indinavir/ritonavir [rate ratio 1.12 (95% CI: 1.04-1.20) per 5 years] remained statistically significant, although effects were small. The strongest independent predictors of hypertension were male gender, older age, black African ethnicity, diabetes, dyslipidaemia, use of lipid-lowering drugs, high body mass index (BMI), renal impairment and a low CD4 count. CONCLUSIONS: We did not find evidence for any strong independent association between exposure to any of the individual ARV drugs and the risk of hypertension. Findings provide reassurance that screening policies and preventative measures for hypertension in HIV-positive persons should follow algorithms used for the general population.

Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma.

Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids.

Predictive value of abdominal CT in evaluating internal herniation after bariatric laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Internal herniation, a serious complication after bariatric surgery, is challenging to diagnose. The aim of this study was to determine the accuracy of abdominal CT in diagnosing internal herniation. METHODS: The study included consecutive patients who had undergone laparoscopic gastric bypass surgery between 1 January 2011 and 1 January 2015 at a bariatric centre of excellence. To select patients suspected of having internal herniation, reports of abdominal CT and reoperations up to 1 January 2017 were screened. CT was presumed negative for internal herniation if no follow-up CT or reoperation was performed within 90 days after the initial CT, or no internal herniation was found during reoperation. The accuracy of abdominal CT in diagnosing internal herniation was calculated using two-way contingency tables. RESULTS: A total of 1475 patients were included (84·7 per cent women, mean age 46·5 years, median initial BMI 41·8 kg/m2 ). CT and/or reoperation was performed in 192 patients (13·0 per cent) in whom internal herniation was suspected. Internal herniation was proven laparoscopically in 37 of these patients. The incidence of internal herniation was 2·5 per cent. An analysis by complaint included a total of 265 episodes, for which 247 CT scans were undertaken. CT was not used to investigate 18 episodes, but internal herniation was encountered in one-third of these during reoperation. Combining the follow-up and intraoperative findings, the accuracy of CT for internal herniation had a sensitivity of 83·8 (95 per cent c.i. 67·3 to 93·2) per cent, a specificity of 87·1 (81·7 to 91·2) per cent, a positive predictive value of 53·4 (40·0 to 66·5) per cent and a negative predictive value of 96·8 (92·9 to 98·7) per cent. CONCLUSION: Abdominal CT is an important tool in diagnosing internal herniation, with a high specificity and a high negative predictive value.