Publications by authors named "Thomas Weber"

561 Publications

Pain in children undergoing tonsillotomy with alternating ibuprofen and paracetamol - a prospective observational study.

Acta Anaesthesiol Scand 2021 Jul 26. Epub 2021 Jul 26.

Department of Otorhinolaryngology, Ruhr-University Bochum, St. Elisabeth-Hospital Bochum, Head & Neck Surgery, Germany.

Background: The optimal pain therapy for children undergoing tonsillotomy remains unknown. Our aim was to evaluate a standard pain therapy including the alternating application of ibuprofen and paracetamol.

Methods: Pain intensity of 81 in-patients after tonsillotomy aged 2 - 12 years was evaluated three times daily (mean observation 3.85 days) using the Children's and Infants' Postoperative Pain Scale (CHIPPS) in children < 5 years, or with the Faces Pain Scale-Revised (FPS-R) in older children. Parents completed the Parents' Postoperative Pain Measure (PPPM-D) in addition. Exceeding the cut-off value in one of the scores implied the indication for an opioid rescue medication (RM). Endpoints were number of children with indication for the RM, course of pain, concordance between pain scales and adverse events.

Results: Overall, 45.7% of children needed the RM either in the recovery room or on the ward. The rate of children having an indication for RM on the ward was 30.9%. The highest proportion of affected children was identified on the day of surgery (32.1%). Most indications were detected with the PPPM-D only. A comparison with an earlier study showed less affected children compared to ibuprofen monotherapy on the day of surgery and the first postoperative day. Eleven children (13.6%) developed fever.

Conclusion: Although our pain therapy concept was effective from postoperative day 1 onwards, it needs improvement for the day of surgery. The overall concordance between the PPPM-D and CHIPPS or FPS-R was low. Fever might be a confounder for the pain intensity measurement with the PPPM-D.
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http://dx.doi.org/10.1111/aas.13959DOI Listing
July 2021

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience.

J Endocr Soc 2021 Sep 2;5(9):bvab099. Epub 2021 Jun 2.

Duke University School of Medicine, Durham, NC 27710, USA.

Purpose: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the nonspecific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO.

Methods: A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA, to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment.

Results: This report provides a summary of our collective experiences in the management of TIO.

Main Conclusions: Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of patients who cannot be operated on with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.
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http://dx.doi.org/10.1210/jendso/bvab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282217PMC
September 2021

Mycotic Popliteal Artery Aneurysm With Rapid Enlargement Post-Bypass.

Cureus 2021 Jun 18;13(6):e15746. Epub 2021 Jun 18.

Surgery, Brooklyn Veterans Affairs Medical Center, Brooklyn, USA.

Popliteal artery aneurysms (PAAs) are the most common type of peripheral artery aneurysms. Mycotic aneurysms involving the popliteal artery are quite rare and can occur as either a primary infection or a secondary infection from another site. To our knowledge, there are no previous case reports on mycotic PAA in which was the primary etiologic pathogen. We present the case of a 55-year-old male who presented with complaints of lower extremity pain and swelling, malaise, and low-grade temperatures for two weeks and was found to have a PAA. He underwent left femoral-popliteal bypass grafting with expanded polytetrafluoroethylene (ePTFE) graft and ligation of the aneurysm. On postoperative day 10, he experienced acute swelling and pain in his lower extremity with foot drop and was found to have rapid enlargement of his aneurysm sac on imaging. He was returned to the operating room emergently where he underwent aneurysmectomy via a posterior fossa approach. Cultures and gram staining of the aneurysm sac were consistent with As noted above, this case of mycotic PAA was treated with standard vascular surgical techniques, yet it proceeded to enlarge acutely. PAAs that rapidly expand or rupture after surgical interventions may be a sign of infection.
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http://dx.doi.org/10.7759/cureus.15746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286778PMC
June 2021

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas.

Blood Adv 2021 07;5(13):2707-2716

Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany.

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
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http://dx.doi.org/10.1182/bloodadvances.2020004155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288676PMC
July 2021

Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action.

Nat Commun 2021 06 18;12(1):3790. Epub 2021 Jun 18.

Department of Biochemistry, University of Zurich, Zurich, Switzerland.

The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model.
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http://dx.doi.org/10.1038/s41467-021-23948-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213836PMC
June 2021

Hypertension and heart failure with preserved ejection fraction: position paper by the European Society of Hypertension.

J Hypertens 2021 Aug;39(8):1522-1545

Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.

Hypertension constitutes a major risk factor for heart failure with preserved ejection fraction (HFpEF). HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality. Specific guideline-directed medical therapy (GDMT) for HFpEF is not established due to lack of positive outcome data from randomized controlled trials (RCTs) and limitations of available studies. Although available evidence is limited, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers provides the backbone of BP-lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, we propose that this core drug treatment strategy is also applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor. In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors, currently already indicated for high-risk patients with diabetes to reduce heart failure hospitalizations, and finerenone represent promising therapies and results from ongoing RCTs are eagerly awaited. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high-quality RCTs are major unmet needs in hypertension research and calls for action.
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http://dx.doi.org/10.1097/HJH.0000000000002910DOI Listing
August 2021

Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension.

Circulation 2021 Jul 3;144(1):52-73. Epub 2021 Jun 3.

Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (M.B., P.M., S.Z., F.E., Y.S., T.W., S.S., L.H.).

Background: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH.

Methods: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo.

Results: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH.

Conclusions: All together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293289PMC
July 2021

Droplets and aerosols: An artificial dichotomy in respiratory virus transmission.

Health Sci Rep 2021 Jun 7;4(2):e275. Epub 2021 May 7.

Joint Research Centre European Commission, Joint Research Centre (JRC) Ispra Italy.

In the medical literature, three mutually non-exclusive modes of pathogen transmission associated with respiratory droplets are usually identified: contact, droplet, and airborne (or aerosol) transmission. The demarcation between droplet and airborne transmission is often based on a cut-off droplet diameter, most commonly 5 μm. We argue here that the infectivity of a droplet, and consequently the transmissivity of the virus, as a function of droplet size is a continuum, depending on numerous factors (gravitational settling rate, transport, and dispersion in a turbulent air jet, viral load and viral shedding, virus inactivation) that cannot be adequately characterized by a single droplet diameter. We propose instead that droplet and aerosol transmission should be replaced by a unique airborne transmission mode, to be distinguished from contact transmission.
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http://dx.doi.org/10.1002/hsr2.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103093PMC
June 2021

'Apples to oranges' and 'Less is more'.

J Hypertens 2021 Jun;39(6):1262-1264

Cardiovascular Prevention and Research Unit, Clinic/Laboratory of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1097/HJH.0000000000002827DOI Listing
June 2021

Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation.

J Am Coll Cardiol 2021 Jun 3;77(23):2909-2919. Epub 2021 May 3.

Department of Medicine, SUNY Downstate College of Medicine, Brooklyn, New York, USA.

Background: The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP.

Objectives: The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN.

Methods: Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models.

Results: Baseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (-0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (-1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN.

Conclusions: Plasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749).
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http://dx.doi.org/10.1016/j.jacc.2021.04.044DOI Listing
June 2021

Spontaneous breathing for managing analgesia during balanced anesthesia with remifentanil and desflurane: a prospective, single center randomized controlled trial.

Med Gas Res 2021 Jul-Sep;11(3):94-99

Department of Anesthesiology and Intensive Care Medicine, St. Josef-Hospital, Ruhr-University of Bochum, Bochum, Germany.

The main goal of anesthesiology is to achieve the best level of analgesia and a fast recovery of consciousness following anesthesia. The preservation of spontaneous breathing during general anesthesia with anesthetic gases is practiced by many anesthetists. However, very few studies have dealt with these positive properties of volatile anesthetics such as sevoflurane or desflurane. Remifentanil is a very short half-life opiate that combines sufficient intra-operative analgesia with a fast post-operative recovery time. We tested the hypothesis that spontaneous breathing can reduce overdosing with remifentanil during desflurane anesthesia. In this prospective, single center, multiple anesthetist study, 30 patients were randomized into two groups (volume-controlled ventilation mode and spontaneous breathing). The spontaneous breathing group showed a significantly lower post-operative pain level than the volume-controlled ventilation mode group. Furthermore, less remifentanil as well as less piritramide was needed in the spontaneous breathing group compared with volume-controlled ventilation mode. It was possible to achieve spontaneous breathing in all patients with 0.6 minimum alveolar concentration desflurane, in order to control the remifentanil rate and prevent an overdose. All spontaneous breathing patients had low intra- and post-operative pain levels and the need for analgesics was equal to or lower than that in the volume-controlled ventilation mode group. By reducing the intra-operative amount of opiates, both the post-operative pain and the amount of post-operative analgesia required can be reduced. A balanced anesthesia with spontaneous intra-operative breathing is needed to determine the required amount of opiates. This study was approved by the Ethic Committee of the Ruhr-University of Bochum (approval No. 2435) in September, 2004.
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http://dx.doi.org/10.4103/2045-9912.310606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174411PMC
May 2021

Acoustic backscattering observations from non-spherical gas bubbles with ka between 0.03 and 4.4.

J Acoust Soc Am 2021 Apr;149(4):2504

Center for Coastal and Ocean Mapping, University of New Hampshire, 24 Colovos Road, Durham, New Hampshire 03824, USA.

The study of gas bubbles in liquid media is of importance in many areas of research. Gas bubbles are often studied using in situ measurement techniques; however, acoustic inversion techniques have also been used to extract physical properties of gas bubbles. These inversion techniques rely on existing analytical scattering models; however, these models often assume that the gas bubbles are spherical in shape and have an equivalent bubble radius, a, that is small compared to the incident acoustic wavelength (ka ≪ 1), which is not always valid. This study aims to understand how the departure from these assumptions affects the acoustic backscattering cross section, σ, of non-spherical gas bubbles. Experimental estimates of σ of non-spherical gas bubbles of different sizes, with ka values ranging between 0.03 and 4.4, were compared to four commonly known analytical σ models. All models performed equally at predicting σ for ka smaller than 0.5; however, there was no model that better predicted the experimental estimates of σ for ka larger than 0.5, regardless of bubble shape. Large variabilities in the experimental estimates of σ are observed for ka larger than 0.5, which are caused by the variability in bubble shape and size, as well as the bubble's orientation.
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http://dx.doi.org/10.1121/10.0004246DOI Listing
April 2021

Correction: Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions.

Gene Ther 2021 Mar 26. Epub 2021 Mar 26.

Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41434-021-00252-yDOI Listing
March 2021

Negative drift of sedation depth in critically ill patients receiving constant minimum alveolar concentration of isoflurane, sevoflurane, or desflurane: a randomized controlled trial.

Crit Care 2021 04 13;25(1):141. Epub 2021 Apr 13.

St. Josef-Hospital, University Hospital of Ruhr-University of Bochum, Bochum, Germany.

Background: Intensive care unit (ICU) physicians have extended the minimum alveolar concentration (MAC) to deliver and monitor long-term volatile sedation in critically ill patients. There is limited evidence of MAC's reliability in controlling sedation depth in this setting. We hypothesized that sedation depth, measured by the electroencephalography (EEG)-derived Narcotrend-Index (burst-suppression N_Index 0-awake N_Index 100), might drift downward over time despite constant MAC values.

Methods: This prospective single-centre randomized clinical study was conducted at a University Hospital Surgical Intensive Care Unit and included consecutive, postoperative ICU patients fulfilling the inclusion criteria. Patients were randomly assigned to receive uninterrupted inhalational sedation with isoflurane, sevoflurane, or desflurane. The end-expiratory concentration of the anaesthetics and the EEG-derived index were measured continuously in time-stamped pairs. Sedation depth was also monitored using Richmond-Agitation-Sedation-Scale (RASS). The paired t-test and linear models (bootstrapped or multilevel) have been employed to analyze MAC, N_Index and RASS across the three groups.

Results: Thirty patients were recruited (female/male: 10/20, age 64 ± 11, Simplified Acute Physiology Score II 30 ± 10). In the first 24 h, 21.208 pairs of data points (N_Index and MAC) were recorded. The median MAC of 0.58 ± 0.06 remained stable over the sedation time in all three groups. The t-test indicated in the isoflurane and sevoflurane groups a significant drop in RASS and EEG-derived N_Index in the first versus last two sedation hours. We applied a multilevel linear model on the entire longitudinal data, nested per patient, which produced the formula N_Index = 43 - 0.7·h (R = 0.76), showing a strong negative correlation between sedation's duration and the N_Index. Bootstrapped linear models applied for each sedation group produced: N_Index of 43-0.9, 45-0.8, and 43-0.4·h for isoflurane, sevoflurane, and desflurane, respectively. The regression coefficient for desflurane was almost half of those for isoflurane and sevoflurane, indicating a less pronounced time-effect in this group.

Conclusions: Maintaining constant MAC does not guarantee stable sedation depth. Thus, the patients necessitate frequent clinical assessments or, when unfeasible, continuous EEG monitoring. The differences across different volatile anaesthetics regarding their time-dependent negative drift requires further exploration.

Trial Registration: NCT03860129.
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http://dx.doi.org/10.1186/s13054-021-03556-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042630PMC
April 2021

Low-temperature (< 200 °C) degradation of electronic nicotine delivery system liquids generates toxic aldehydes.

Sci Rep 2021 Apr 8;11(1):7800. Epub 2021 Apr 8.

Pacific Northwest National Laboratory, Richland, WA, 99354, USA.

Electronic cigarette usage has spiked in popularity over recent years. The enhanced prevalence has consequently resulted in new health concerns associated with the use of these devices. Degradation of the liquids used in vaping have been identified as a concern due to the presence of toxic compounds such as aldehydes in the aerosols. Typically, such thermochemical conversions are reported to occur between 300 and 400 °C. Herein, the low-temperature thermal degradation of propylene glycol and glycerol constituents of e-cigarette vapors are explored for the first time by natural abundance C NMR and H NMR, enabling in situ detection of intact molecules from decomposition. The results demonstrate that the degradation of electronic nicotine delivery system (ENDS) liquids is strongly reliant upon the oxygen availability, both in the presence and absence of a material surface. When oxygen is available, propylene glycol and glycerol readily decompose at temperatures between 133 and 175 °C over an extended time period. Among the generated chemical species, formic and acrylic acids are observed which can negatively affect the kidneys and lungs of those who inhale the toxin during ENDS vapor inhalation. Further, the formation of hemi- and formal acetals is noted from both glycerol and propylene glycol, signifying the generation of both formaldehyde and acetaldehyde, highly toxic compounds, which, as a biocide, can lead to numerous health ailments. The results also reveal a retardation in decomposition rate when material surfaces are prevalent with no directly observed unique surface spectator or intermediate species as well as potentially slower conversions in mixtures of the two components. The generation of toxic species in ENDS liquids at low temperatures highlights the dangers of low-temperature ENDS use.
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http://dx.doi.org/10.1038/s41598-021-87044-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032854PMC
April 2021

Teriflunomide provides protective properties after oxygen-glucose-deprivation in hippocampal and cerebellar slice cultures.

Neural Regen Res 2021 Nov;16(11):2243-2249

Institute of Anatomy, Department of Cytology, Medical Faculty, Ruhr University Bochum, Bochum, Germany.

One of the major challenges in emergency medicine is out-of-hospital cardiac arrest (OHCA). Every year, about 53-62/100 000 people worldwide suffer an out-of-hospital cardiac arrest with serious consequences, whereas persistent brain injury is a major cause of morbidity and mortality of those surviving a cardiac arrest. Today, only few and insufficient strategies are known to limit neurological damage of ischemia and reperfusion injury. The aim of the present study was to investigate whether teriflunomide, an approved drug for treatment of relapsing-remitting-multiple-sclerosis, exerts a protective effect on brain cells in an in vitro model of ischemia. Therefore, organotypic slice cultures from rat hippocampus and cerebellum were exposed to oxygen-glucose-deprivation and subsequently treated with teriflunomide. The administration of teriflunomide in the reperfusion time on both hippocampal and cerebellar slice cultures significantly decreased the amount of detectable propidium iodide signal compared with an untreated culture, indicating that more cells survive after oxygen-glucose-deprivation. However, hippocampal slice cultures showed a higher vulnerability to ischemic conditions and a more sensitive response to teriflunomide compared with cerebellar slice cultures. Our study suggests that teriflunomide, applied as a post-treatment after an oxygen-glucose-deprivation, has a protective effect on hippocampal and cerebellar cells in organotypic slice cultures of rats. All procedures were conducted under established standards of the German federal state of North Rhine Westphalia, in accordance with the European Communities Council Directive 2010/63/EU on the protection of animals used for scientific purposes.
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http://dx.doi.org/10.4103/1673-5374.310689DOI Listing
November 2021

Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions.

Authors:
Thomas Weber

Front Immunol 2021 17;12:658399. Epub 2021 Mar 17.

Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Adeno-associated virus (AAV) vector-based gene therapy is currently the only gene therapy approved in the US and Europe. The recent tragic death of three children in a clinical trial to treat X-Linked Myotubular Myopathy by delivering myotubularin with an AAV8 vector notwithstanding, AAV remains a highly promising therapeutic gene delivery platform. But the successful use of AAV vectors to treat an increasing number of diseases also makes establishing protocols to determine therapeutically relevant titers of pre-existing anti-AAV antibodies and approaches to deplete those antibodies more urgent than ever. In this mini review, I will briefly discuss (i) our knowledge regarding the prevalence of anti-AAV antibodies, (ii) the challenges to measure those antibodies by methods that are most predictive of their influence on therapeutic efficacy of AAV gene transfer, and (iii) approaches to overcome the formidable hurdle that anti-AAV antibodies pose to the successful clinical use of AAV gene therapy.
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http://dx.doi.org/10.3389/fimmu.2021.658399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010240PMC
March 2021

Retrospective cross sectional analysis of demographic disparities in outcomes of CPR performed by EMS providers in the United States.

JRSM Cardiovasc Dis 2021 Jan-Dec;10:20480040211000619. Epub 2021 Mar 10.

California Northstate University College of Medicine, Elk Grove, CA, USA.

Objective: To investigate demographic disparities in prehospital cardiopulmonary resuscitation (CPR) initiation and successful outcomes of patients with out-of-hospital cardiac arrest (OHCA) treated by emergency medical services (EMS) providers.

Methods: We analyzed the National Emergency Medical Service Information Systems (NEMSIS) 2017 database, analyzing patient gender, age and race against CPR initiation and Return of Spontaneous Circulation (ROSC). The analysis was performed for a subset of patients who received bystander interventions (n = 3,362), then repeated for the whole cohort of patients (n = 5,833).

Results: Within the subgroup of patients that received CPR or AED application prior to the arrival of the paramedics, a logistic regression for CPR initiation rates as a function of race, gender and age reported the following adjusted odds ratios: African American (AA) to White 0.570 (95%CI [0.419, 0.775]), Hispanic to White 0.735 (95%CI [0.470, 1.150]); female to male 0.768 (95%CI [0.598, 0.986]); senior to adult 0.708 (95%CI [0.545, 0.920). Similarly, a logistic regression of ROSC as a function of race, gender and age reported the following adjusted odds ratios: AA to White 0.652 (95%CI [0.533, 0.797]) Hispanic to White 1.018 (95%CI [0.783, 1.323]); female to male 0.887 (95%CI [0.767, 1.025]); senior to adult 0.817 (95%CI [0.709, 0.940]). Similar trends existed in the entire cohort of patients.

Conclusions: These results suggest that there are discrepancies in patient care during cardiopulmonary arrest performed by EMS for OHCA, inviting further exploration of healthcare differences in the prehospital EMS approach to OHCA.
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http://dx.doi.org/10.1177/20480040211000619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961709PMC
March 2021

Highly parallelized droplet cultivation and prioritization of antibiotic producers from natural microbial communities.

Elife 2021 03 25;10. Epub 2021 Mar 25.

Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.

Antibiotics from few culturable microorganisms have saved millions of lives since the 20th century. But with resistance formation, these compounds become increasingly ineffective, while the majority of microbial and with that chemical compound diversity remains inaccessible for cultivation and exploration. Culturing recalcitrant bacteria is a stochastic process. But conventional methods are limited to low throughput. By increasing (i) throughput and (ii) sensitivity by miniaturization, we innovate microbiological cultivation to comply with biological stochasticity. Here, we introduce a droplet-based microscale cultivation system, which is directly coupled to a high-throughput screening for antimicrobial activity prior to strain isolation. We demonstrate that highly parallelized in-droplet cultivation starting from single cells results in the cultivation of yet uncultured species and a significantly higher bacterial diversity than standard agar plate cultivation. Strains able to inhibit intact reporter strains were isolated from the system. A variety of antimicrobial compounds were detected for a selected potent antibiotic producer.
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http://dx.doi.org/10.7554/eLife.64774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081529PMC
March 2021

CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037;

Through dominant mutations, aminoacyl-tRNA synthetases constitute the largest protein family linked to Charcot-Marie-Tooth disease (CMT). An example is CMT subtype 2N (CMT2N), caused by individual mutations spread out in AlaRS, including three in the aminoacylation domain, thereby suggesting a role for a tRNA-charging defect. However, here we found that two are aminoacylation defective but that the most widely distributed R329H is normal as a purified protein in vitro and in unfractionated patient cell samples. Remarkably, in contrast to wild-type (WT) AlaRS, all three mutant proteins gained the ability to interact with neuropilin 1 (Nrp1), the receptor previously linked to CMT pathogenesis in GlyRS. The aberrant AlaRS-Nrp1 interaction is further confirmed in patient samples carrying the R329H mutation. However, CMT2N mutations outside the aminoacylation domain do not induce the Nrp1 interaction. Detailed biochemical and biophysical investigations, including X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange (HDX), switchSENSE hydrodynamic diameter determinations, and protease digestions reveal a mutation-induced structural loosening of the aminoacylation domain that correlates with the Nrp1 interaction. The b1b2 domains of Nrp1 are responsible for the interaction with R329H AlaRS. The results suggest Nrp1 is more broadly associated with CMT-associated members of the tRNA synthetase family. Moreover, we revealed a distinct structural loosening effect induced by a mutation in the editing domain and a lack of conformational impact with C-Ala domain mutations, indicating mutations in the same protein may cause neuropathy through different mechanisms. Our results show that, as with other CMT-associated tRNA synthetases, aminoacylation per se is not relevant to the pathology.
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http://dx.doi.org/10.1073/pnas.2012898118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020758PMC
March 2021

Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions.

Gene Ther 2021 Mar 3. Epub 2021 Mar 3.

Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

In the last two decades, recombinant adeno-associated virus has emerged as the most popular gene therapy vector. Recently AAV gene therapy has been approved by the FDA for the treatment of two rare genetic disorders, namely the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). As is the case for the treatment of SMA, if the AAV vector must be administered systemically, very high vector doses are often required for therapeutic efficacy. But higher vector doses inevitably increase the risk of adverse events. The tragic death of three children in a clinical trial to treat X-linked myotubular myopathy with an AAV vector has thrown this limitation into sharp relief. Regardless of the precise cause(s) that led to the death of the two children, it is critical that we develop better AAV vectors to achieve therapeutic levels of expression with lower vector doses. To transduce successfully a target cell, AAV has to overcome both systemic as well as cellular roadblocks. In this review, we discuss some of the most prominent cellular roadblocks that AAV must get past to deliver successfully its therapeutic payload. We also highlight recent advancements in our knowledge of AAV biology that can potentially be harnessed to improve AAV vector performance and thereby make AAV gene therapy safer.
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http://dx.doi.org/10.1038/s41434-021-00243-zDOI Listing
March 2021

Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness.

Front Mol Neurosci 2020 7;13:600051. Epub 2021 Jan 7.

Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.

Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (KO) mice. Here, we employed and approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length coding sequence. Upon early postnatal injection into the cochlea of KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9-using a single overloaded AAV vector-is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches.
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http://dx.doi.org/10.3389/fnmol.2020.600051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817888PMC
January 2021

Tough metal-ceramic composites with multifunctional nacre-like architecture.

Sci Rep 2021 Jan 15;11(1):1621. Epub 2021 Jan 15.

Complex Materials, Department of Materials, ETH Zürich, 8093, Zurich, Switzerland.

The brick-and-mortar architecture of biological nacre has inspired the development of synthetic composites with enhanced fracture toughness and multiple functionalities. While the use of metals as the "mortar" phase is an attractive option to maximize fracture toughness of bulk composites, non-mechanical functionalities potentially enabled by the presence of a metal in the structure remain relatively limited and unexplored. Using iron as the mortar phase, we develop and investigate nacre-like composites with high fracture toughness and stiffness combined with unique magnetic, electrical and thermal functionalities. Such metal-ceramic composites are prepared through the sol-gel deposition of iron-based coatings on alumina platelets and the magnetically-driven assembly of the pre-coated platelets into nacre-like architectures, followed by pressure-assisted densification at 1450 °C. With the help of state-of-the-art characterization techniques, we show that this processing route leads to lightweight inorganic structures that display outstanding fracture resistance, show noticeable magnetization and are amenable to fast induction heating. Materials with this set of properties might find use in transport, aerospace and robotic applications that require weight minimization combined with magnetic, electrical or thermal functionalities.
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http://dx.doi.org/10.1038/s41598-021-81068-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810751PMC
January 2021

Lifestyle, psychological, socioeconomic and environmental factors and their impact on hypertension during the coronavirus disease 2019 pandemic.

J Hypertens 2021 06;39(6):1077-1089

Department of Hypertension, National Institute of Cardiology, Warsaw, Poland.

Summary: The coronavirus disease 2019 (COVID-19) pandemic considerably affects health, wellbeing, social, economic and other aspects of daily life. The impact of COVID-19 on blood pressure (BP) control and hypertension remains insufficiently explored. We therefore provide a comprehensive review of the potential changes in lifestyle factors and behaviours as well as environmental changes likely to influence BP control and cardiovascular risk during the pandemic. This includes the impact on physical activity, dietary patterns, alcohol consumption and the resulting consequences, for example increases in body weight. Other risk factors for increases in BP and cardiovascular risk such as smoking, emotional/psychologic stress, changes in sleep patterns and diurnal rhythms may also exhibit significant changes in addition to novel factors such as air pollution and environmental noise. We also highlight potential preventive measures to improve BP control because hypertension is the leading preventable risk factor for worldwide health during and beyond the COVID-19 pandemic.
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http://dx.doi.org/10.1097/HJH.0000000000002770DOI Listing
June 2021

Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements.

Hypertension 2021 02 4;77(2):632-639. Epub 2021 Jan 4.

From the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia (D.S.P., M.G.S., M.K.A., J.A.B., N.D., P.R.-T., J.E.S.).

Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16109DOI Listing
February 2021

Aortic Pulse Wave Velocity Predicts Cardiovascular Events and Mortality in Patients Undergoing Coronary Angiography: A Comparison of Invasive Measurements and Noninvasive Estimates.

Hypertension 2021 02 4;77(2):571-581. Epub 2021 Jan 4.

Klinikum Wels-Grieskirchen, Cardiology Department, Wels, Austria (K.D., R.K.B., T.W.).

Aortic pulse wave velocity (PWV) is directly related to arterial stiffness. Different methods for the determination of PWV coexist. The aim of this prospective study was to evaluate the prognostic value of PWV in high-risk patients with suspected coronary artery disease undergoing invasive angiography and to compare 3 different methods for assessing PWV. In 1040 patients, invasive PWV (iPWV) was measured during catheter pullback. Additionally, PWV was estimated with a model incorporating age, central systolic blood pressure, and pulse waveform characteristics obtained from noninvasive measurements (estimated PWV). As a third method, PWV was calculated with a formula solely based on age and blood pressure (formula-based PWV). Survival analysis was based on continuous PWV as well as using cutoff values. After a median follow-up duration of 1565 days, 24% of the patients reached the combined end point (cardiovascular events or mortality). Cox proportional hazard ratios per 1 SD were 1.35 for iPWV, 1.37 for estimated PWV, and 1.28 for formula-based PWV (<0.0001 for all 3 methods) in univariate analysis, remaining statistically significant after comprehensive multivariable adjustments. In a model including a modified risk score for coronary artery disease, iPWV and estimated PWV remained borderline significant. The net reclassification improvement was significant for iPWV (0.173), formula-based PWV (0.181), and estimated PWV (0.230). All 3 methods for the determination of PWV predicted cardiovascular events and mortality in patients with suspected coronary artery disease. This indicates that iPWV as well as both noninvasive estimation methods are suitable for the assessment of arterial stiffness, bearing in mind their individual characteristics.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15336DOI Listing
February 2021

A phantom study on dose efficiency for orthopedic applications: Comparing slot-scanning radiography using ultra-small-angle tomosynthesis to conventional radiography.

Med Phys 2021 May 30;48(5):2170-2184. Epub 2021 Mar 30.

Pattern Recognition Lab, Friedrich-Alexander University Erlangen-Nürnberg, Martensstr. 3, Erlangen, 91058, Germany.

Purpose: This paper studies the abilities of a twin-robotic x-ray slot-scanning system for orthopedic imaging to reduce dose by scatter rejection compared to conventional digital radiography.

Methods: We investigate the dose saving capabilities, especially in terms of the signal- and the contrast-to-noise ratio, as well as the scatter-to-primary ratio of the proposed slot-scanning method in comparison to the state-of-the-art method for length-extended imaging. As a baseline, we use x-ray parameters of two clinically established acquisition protocols that provide the same detector entrance dose but are profoundly different in patient dose. To obtain an estimate of the photon-related noise directly from an x-ray image, we implement a Poisson-Gaussian noise model. This model is used to compare the dose efficiency of two settings and combined with the well-known to determine the transmission parameters. We present a method with an associated measurement protocol, utilizing the robotic capabilities of the used system to automatically obtain quasi-scatter-free ground-truth data with exact geometric correspondence to full-field and slot acquisitions. In total, we investigate two body regions (thoracic spine and lumbar spine) in anterior-posterior view with two patient sizes (BMI = 22 and 30) in two acquisition modes (conventional and slot scan with a flat-panel detector) with and without anti-scatter grid using an anthropomorphic upper-body phantom.

Results: We have shown that it is feasible to combine the proposed approach with the for the determination of scatter rejection parameters. The use of an anti-scatter grid is indicated for full-field acquisitions allowing for dose savings up to 46% compared to their gridless counterparts. When changing the acquisition mode to the investigated slot scan, the use of an anti-scatter grid has no major impact on the image quality in terms of dose efficiency, in particular for patients with a BMI of 22. However, an increased contrast improvement factor was found. For normal-sized patients, up to 53% of dose can be saved additionally in comparison to full-field acquisitions with grid. Moreover, we could demonstrate that a slot size of 5 cm and air gap of 10 cm is sufficient to achieve scatter-to-primary ratios, which are equal or better compared to those of the full-field acquisitions with a grid.

Conclusions: We have shown, that the slot-scanning approach is always superior to the conventional full-field acquisition in terms of signal-to-noise and scatter-to-primary ratios. Compared to the state-of-the-art acquisition protocols with a grid, dose savings up to 53% are possible due to the scatter rejection without compromising the SNR. Hence, the use of the slot-scanning method is indicated, especially when it comes to regularly carried-out follow-up acquisitions, for example, in the case of scoliosis monitoring.
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http://dx.doi.org/10.1002/mp.14680DOI Listing
May 2021

In vitro performance evaluation of AnaConDa-100 and AnaConDa-50 compared to a circle breathing system for control and consumption of volatile anaesthetics.

J Clin Monit Comput 2020 Dec 21. Epub 2020 Dec 21.

Department of Anaesthesiology and Intensive Care Medicine, Ruhr-University Bochum, St. Josef Hospital, Gudrunstraße 56, 44791, Bochum, Germany.

To identify the better volatile anaesthetic delivery system in an intensive care setting, we compared the circle breathing system and two models of reflection systems (AnaConDa™ with a dead space of 100 ml (ACD-100) or 50 ml (ACD-50)). These systems were analysed for the parameters like wash-in, consumption, and wash-out of isoflurane and sevoflurane utilising a test lung model. The test lung was connected to a respirator (circle breathing system: Aisys CS™; ACD-100/50: Puriton Bennett 840). Set parameters were volume-controlled mode, tidal volume-500 ml, respiratory rate-10/min, inspiration time-2 sec, PEEP-5 mbar, and oxygen-21%. Wash-in, consumption, and wash-out were investigated at fresh gas flows of 0.5, 1.0, 2.5, and 5.0 l/min. Anaesthetic target concentrations were 0.5, 1.0, 1.5, 2.0, and 2.5%.  Wash-in was slower in ACD-100/-50 compared to the circle breathing system, except for fresh gas flows of 0.5 and 1.0 l/min. The consumption of isoflurane and sevoflurane in ACD-100 and ACD-50 corresponded to the fresh gas flow of 0.5-1.0 l/min in the circle breathing system. Consumption with ACD-50 was higher in comparison to ACD-100, especially at gas concentrations > 1.5%. Wash-out was quicker in ACD-100/-50 than in the circle breathing system at a fresh gas flow of 0.5 l/min, however, it was longer at all the other flow rates. Wash-out was comparable in ACD-100 and ACD-50. Wash-in and wash-out were generally quicker with the circle breathing system than in ACD-100/-50. However, consumption at 0.5 minimum alveolar concentration was comparable at flows of 0.5 and 1.0 l/min.
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http://dx.doi.org/10.1007/s10877-020-00634-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751266PMC
December 2020

Burosumab for the Treatment of Tumor-Induced Osteomalacia.

J Bone Miner Res 2021 Apr 12;36(4):627-635. Epub 2021 Jan 12.

Yale University School of Medicine, New Haven, CT, USA.

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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http://dx.doi.org/10.1002/jbmr.4233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247961PMC
April 2021
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