Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Quantitative biosensor detection by chemically exchanging hyperpolarized 129Xe.

Chemical sensors informing about their local environment are of widespread use for chemical analysis. A thorough understanding of the sensor signaling is fundamental to data analysis and interpretation, and a requirement for technological applications. Here, sensors explored for the recognition and display of biomolecular and cellular markers by magnetic resonance and composed of host molecules for xenon atoms are considered. These host-guest systems are analytically powerful and also function as contrast agents in imaging applications. Using nuclear spin hyperpolarization of 129Xe and chemical exchange saturation transfer the detection sensitivity is orders of magnitude enhanced in comparison to conventional 1H NMR. The sensor signaling reflects this rather complex genesis, furthering the mere qualitative interpretation of biosensing data; to harvest the potential of the approach, however, a detailed numerical account is desired. To this end, we introduce a comprehensive expression that maps the sensor detection quantitatively by integration of the hyperpolarization generation and relaxation with the host-xenon exchange dynamics. As demonstrated for the host molecule and well-established biosensor cryptophane-A, this model reveals a distinguished maximum in sensor signaling and exerts control over experimentation by dedicated adjustments of both the amount of xenon and the duration of the saturation transfer applied in a measurement, for example to capitalize on investigations at the detection limit. Furthermore, usage of the model for data analysis makes the quantification of the sensor concentration in the nanomolar range possible. The approach is readily applicable in investigations using cryptophane-A and is straightaway adaptable to other sensor designs for extension of the field of xenon based biosensing.

AN ESTIMATION OF THE EXPOSURE OF THE POPULATION OF ISRAEL TO NATURAL SOURCES OF IONIZING RADIATION.

The radiation dose to the population of Israel due to exposure to natural sources of ionizing radiation was assessed. The main contributor to the dose is radon that accounts for 60% of the exposure to natural sources. The dose due to radon inhalation was assessed by combining the results of a radon survey in single-family houses with the results of a survey in apartments in multi-storey buildings. The average annual dose due to radon inhalation was found to be 1.2 mSv. The dose rate due to exposure to cosmic radiation was assessed using a code that calculates the dose rate at different heights above sea level, taking into account the solar cycle. The annual dose was calculated based on the fraction of time spent indoors and the attenuation provided by buildings and was found to be 0.2 mSv. The annual dose due to external exposure to the terrestrial radionuclides was similarly assessed. The indoor dose rate was calculated using a model that takes into account the concentrations of the natural radionuclides in building materials, the density and the thickness of the walls. The dose rate outdoors was calculated based on the concentrations of the natural radionuclides in different geological units in Israel as measured in an aerial survey and measurements above ground. The annual dose was found to be 0.2 mSv. Doses due to internal exposure other than exposure to radon were also calculated and were found to be 0.4 mSv. The overall annual exposure of the population of Israel to natural sources of ionizing radiation is therefore 2 mSv and ranges between 1.7 and 2.7 mSv.

Smoking Lung Cancer Patients and Tobacco Cessation - Is the Current Treatment in Germany Sufficient?

Lung cancer is the most preventable neoplastic disease for men and women. The incidence rate per year is 14.000 in Germany. Smoking is the main risk factor for the onset of lung cancer and for a share of 90% of cases, lung cancer is associated with smoking. Recent studies have shown that the time slot of diagnosing lung cancer is a teachable moment for tobacco cessation interventions. The therapy that was rated most effective was a combination of cognitive behavioral therapy and pharmacotherapy (e. g. NRT, Bupropion, Varenicline). We examined the smoking status of all patients undergoing lung cancer surgery in 2011, 2012 and 2013 in this study. A retrospective semi structured interview via telephone was conducted regarding smoking habits and current quality of life. 131 patients (36.6% female, average age of 68.7 years) of an urban German hospital were included.Results showed a relapse rate of 22.3%, while 86.2% used to be highly addicted smokers; A multivariate analysis of covariance (MANCOVA) indicated a significant overall impact of smoking status on quality of life with a medium effect size, controlled for age, gender, living conditions, tumor stage, duration of smoking abstinence, type of cancer therapy, type of resection method, and the time period between the date of surgery and of the survey. Two thirds of all smokers did not see an association between their habit and their disease.So far motivation to quit and long term abstinence rates are not sufficiently established even among seriously sick patients in Germany; further initiatives should focus on new and more intense interventions and educational strategies.

The impact of age on the benefits and risks of aliskiren treatment: analyses of the 3A registry.

We aimed to analyze benefits and risks of aliskiren treatment in older adults (⩾ 65 years) in clinical practice. Patients (n = 14,986) were assigned to either aliskiren (ALIS), an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB), or an agent not blocking the renin-angiotensin system (non-RAS). Older adults (n = 7396) had a longer history of hypertension (8.7 vs 4.7 years; P < 0.0001), lower mean diastolic blood pressure (DBP; 87.7 ± 11.0 vs 92.1 ± 11.0 mm Hg) and more renal (12.0 vs 5.6%; P < 0.0001) or cardiovascular disease (44.0 vs 18.9%; P < 0.0001); 4548 received aliskiren (68.8%), 1215 ACEi/ARBs (18.4%) and 850 non-RAS treatments (12.9%). Office BP at 1 year was reduced by 18.4 ± 21.5/7.2 ± 12.0 mm Hg. BP reductions were greater (19.5 ± 21.7/7.6 ± 12.1 mm Hg) in the aliskiren group than in the ACEi/ARB (15.6 ± 20.9/6.4 ± 11.9) and non-RAS groups (16.1 ± 20.7/6.5 ± 11.7 mm Hg), respectively (P<0.0001 for systolic BP (SBP) and <0.01 for DBP). After multivariable adjustment, differences in SBP reductions were clinically irrelevant and no differences were noted for DBP. Adverse effects were higher in older adults with no differences between treatment groups. In conclusion, the present analysis of a large, unselected cohort of patients in clinical practice from the 3A study, offers real-life evidence of the effectiveness and safety of aliskiren for the treatment of hypertension in older adults.

Radon concentrations in different types of dwellings in Israel.

The average radon concentration in Israeli dwellings was assessed by combining the results of a 2006 radon survey in single-family houses with the results of a 2011 radon survey in apartments of multistorey buildings. Both surveys were based on long-term measurements using CR-39 detectors. The survey in multistorey buildings was intended to assess the influence of recent practices in the local building industry on the radon concentrations. These practices include the use of building materials with higher concentrations of the natural radionuclides in the last 20 y than before, as well as the improvement in sealing techniques over that period. Another practice in place since the early 1990 s is the building of a shielded area in every apartment that is known as an RSS (residential secure space). The RSS is a room built from massive concrete walls, floor and ceiling that can be hermetically sealed and is intended to protect its residents from a missile attack. The influence of the above-mentioned features on radon concentrations was estimated by dividing the participating apartments into two groups: apartments in buildings >20 y, built using building materials with low concentrations of the natural radionuclides, regular sealing and without an RSS and apartments in buildings newer than 10 y, built using building materials with higher concentrations of the natural radionuclides, improved sealing and including an RSS. It was found that the average radon concentration in apartments in new buildings was significantly higher than in old buildings and the average radon concentration in single-family houses was significantly higher than in apartments in multistorey buildings. Doses due to indoor radon were estimated on the basis of the updated information included in the 2009 International Commission on Radiological Protection statement on radon.

Tracing catalytic conversion on single zeolite crystals in 3D with nonlinear spectromicroscopy.

The cost- and material-efficient development of next-generation catalysts would benefit greatly from a molecular-level understanding of the interaction between reagents and catalysts in chemical conversion processes. Here, we trace the conversion of alkene and glycol in single zeolite catalyst particles with unprecedented chemical and spatial resolution. Combined nonlinear Raman and two-photon fluorescence spectromicroscopies reveal that alkene activation constitutes the first reaction step toward glycol etherification and allow us to determine the activation enthalpy of the resulting carbocation formation. Considerable inhomogeneities in local reactivity are observed for micrometer-sized catalyst particles. Product ether yields observed on the catalyst are ca. 5 times higher than those determined off-line. Our findings are relevant for other heterogeneous catalytic processes and demonstrate the immense potential of novel nonlinear spectromicroscopies for catalysis research.

Current CONtrolled Transmit And Receive Coil Elements (CONTAR) for Parallel Acquisition and Parallel Excitation Techniques at High-Field MRI.

A novel intrinsically decoupled transmit and receive radio-frequency coil element is presented for applications in parallel imaging and parallel excitation techniques in high-field magnetic resonance imaging. Decoupling is achieved by a twofold strategy: during transmission elements are driven by current sources, while during signal reception resonant elements are switched to a high input impedance preamplifier. To avoid B(0) distortions by magnetic impurities or DC currents a resonant transmission line is used to relocate electronic components from the vicinity of the imaged object. The performance of a four-element array for 3 T magnetic resonance tomograph is analyzed by means of simulation, measurements of electromagnetic fields and bench experiments. The feasibility of parallel acquisition and parallel excitation is demonstrated and compared to that of a conventional power source-driven array of equivalent geometry. Due to their intrinsic decoupling the current-controlled elements are ideal basic building blocks for multi-element transmit and receive arrays of flexible geometry.

Genetic algorithm for shift-uncertainty correction in 1-D NMR-based metabolite identifications and quantifications.

MOTIVATION: The analysis of metabolic processes is becoming increasingly important to our understanding of complex biological systems and disease states. Nuclear magnetic resonance spectroscopy (NMR) is a particularly relevant technology in this respect, since the NMR signals provide a quantitative measure of the metabolite concentrations. However, due to the complexity of the spectra typical of biological samples, the demands of clinical and high-throughput analysis will only be fully met by a system capable of reliable, automatic processing of the spectra. An initial step in this direction has been taken by Targeted Profiling (TP), employing a set of known and predicted metabolite signatures fitted against the signal. However, an accurate fitting procedure for (1)H NMR data is complicated by shift uncertainties in the peak systems caused by measurement imperfections. These uncertainties have a large impact on the accuracy of identification and quantification and currently require compensation by very time consuming manual interactions. Here, we present an approach, termed Extended Targeted Profiling (ETP), that estimates shift uncertainties based on a genetic algorithm (GA) combined with a least squares optimization (LSQO). The estimated shifts are used to correct the known metabolite signatures leading to significantly improved identification and quantification. In this way, use of the automated system significantly reduces the effort normally associated with manual processing and paves the way for reliable, high-throughput analysis of complex NMR spectra. RESULTS: The results indicate that using simultaneous shift uncertainty correction and least squares fitting significantly improves the identification and quantification results for (1)H NMR data in comparison to the standard targeted profiling approach and compares favorably with the results obtained by manual expert analysis. Preservation of the functional structure of the NMR spectra makes this approach more realistic than simple binning strategies.

Differently complex oligosaccharides can be easily identified by matrix-assisted laser desorption and ionization time-of-flight mass spectrometry directly from a standard thin-layer chromatography plate.

Thin-layer chromatography (TLC) is a simple, fast and inexpensive separation method. Unambiguous identification of the TLC spots is, however, often a problem. Here we show for the first time that oligosaccharides (derived from dextran, alginate, hyaluronan and chondroitin sulfate) can be characterized by matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) directly on a TLC plate. The applied oligosaccharides were either commercially available or obtained from the polysaccharides by HCl-induced hydrolysis. Normal phase TLC was followed by MALDI-TOF MS subsequent to matrix deposition. It will be shown that high quality mass spectra can be obtained that enable unequivocal assignments. It will also be shown that the high content of formic acid in the solvent system does not confer major problems but is responsible for the partial formylation of the analyte and minor N-acetyl loss from hyaluronan and chondroitin sulfate.

The decision making process on public health measures related to passenger ships: the example of influenza pandemic 2009.

BACKGROUND: Public health measures at sea ports have posed a challenge for public health competent authorities, especially in the context of the influenza pandemic of 2009. This paper discusses the response of authorities to notifications of infectious diseases on passenger ships and the importance of assessing the risks related to cases of influenza. It further provides options for health measures and considerations for decision making during a pandemic such as the influenza pandemic of 2009. DISCUSSION: Prevention and control of influenza have included action taken by both competent port authorities and ships' crews. Assessing the public health risk of each event reported from ships to competent authorities at ports is important before advice is given on implementation of control measures. Public health risk assessment involves appraisal of threats to passengers and crew on board the ship as well as to the population in the community. SUMMARY: Any public health measures taken should be necessary and proportional to the threat. Measures at ports cannot alone be effective in the prevention of the spread of a disease to the community since other means of transport play a major role. Measures taken on board ships can be effective in containing the disease. Consistent policy based on common protocols and carried out by competent authorities at local, national, European, or international levels are essential.

Preparedness for the prevention and control of influenza outbreaks on passenger ships in the EU: the SHIPSAN TRAINET project communication.

Passenger ships carry a large number of people in confined spaces. A case of the new influenza A (H1N1) virus aboard a passenger ship is an expected event and would lead to rapid spread of the virus, if preventive measures are not in place. However, many cruise lines have detailed policies and procedures to deal with cases of influenza like illness (ILI). The EU SHIPSAN and SHIPSAN TRAINET projects include in their objectives guidelines for the prevention and control of communicable diseases aboard passenger ships. A literature review showed that from 1997 to 2005, nine confirmed outbreaks of influenza were linked to passenger ships, with attack rates up to 37%. It is important to establish and maintain a surveillance system for ILI aboard passenger ships, in order to systematically collect data that can help to determine the baseline illness levels. Monitoring these will enable early identification of outbreaks and allow timely implementation of control measures.

Quantitative assessment of optic nerve head pallor.

Ischaemia, loss of neural tissue, glial cell activation and tissue remodelling are symptoms of anterior ischaemic as well as glaucomatous optic neuropathy leading to pallor of the optic nerve head. Here, we describe a simple method for the pallor measurement using a fundus camera equipped with a colour CCD camera and a special dual bandpass filter. The reproducibility of the determined mean pallor value was 11.7% (coefficient of variation for repeated measurements in the same subject); the variation over six healthy subjects was 14.8%. A significant difference between the mean pallor of an atrophic disc and that of the contralateral eye of the same individual was found. However, even the clinically unaffected eye showed a significantly increased pallor compared to the mean of the healthy control group. Thus, optic disc pallor measurement, as described here, may be helpful in the early detection and follow-up of optic neuropathy.

[Static vessel analysis in nonmydriatic and mydriatic images]. / Statische Gefässanalyse in nonmydriatischen und mydriatischen Bildern.

BACKGROUND: Static vessel analysis is a method to determine the diameter of retinal vessels in images of the ocular fundus. The suitability of non-mydriatic and mydriatic images for that method and the influence of mydriasis on the results were examined. MATERIALS AND METHODS: In the prospective study, 30 eyes of 15 patients (10 women, mean age 51.6 +/- 13.2 years) were examined. At first, 3 images were taken of each eye with the retinal camera Topcon NW 200 (magnification 1). After pupil dilation with tropicamid eye drops, 3 more images were taken using the Topcon and 3 others using the system Visualis (IMEDOS, Jena/Germany, FF450plus, 535-561 nm, 30 degrees image, 1840 x 1360 pixel). The vessel diameters were measured with the software Vesselmap2 (IMEDOS). The investigator assigned vessels to arteries or veins and their diameters were calculated automatically by the software. There is the possibility to define the vessel edge manually in cases of a poor image quality. The calculation of the central retinal arterial and venous equivalent (CRAE, CRVE) as well as the arterio-venous ratio (AVR) were made according to the formula of Parr-Hubbard. Furthermore, the nasal retinal vessels > 60 microm were examined to estimate the influence of tropicamid on the vessel diameter. RESULTS: Because of insufficient illumination and poor contrast in 21 % of the non-mydriatic images not all vessels could be detected automatically. Additionally, fewer vessels could be detected in 7 % of the non-mydriatic images compared to the mydriatic images. The average coefficient of variation of CRAE and AVR of each triplet of images was higher in non-mydriatic images (2.6 % and 3.2 %, respectively) than in mydriatic images of the Topcon (1.8 %; 2.3 %) and the FF 450 (1.7 %; 1.8 % ANOVA p < 0.05). No significant differences were found between the various examination methods for both the coefficient of variation of CRVE (1.9 %; 1.8 %; 1.7 %) and the average values of CRAE, CRVE and AVR. With regard to their diameters, the nasal retinal arteries and veins > 60 microm, were depicted sufficiently in all images, and only differed insignificantly between the three methods. CONCLUSION: The quality of non-mydriatic images is often lower than that of mydriatic images. This fact can account for the high variance of measured parameters in the non-mydriatic images. The depiction of all relevant vessel segments is a precondition for the image-based analysis. An influence of the mydriasis caused by tropicamid on the retinal vessel diameters > 60 microm was not found.

Blood pressure effects on retinal vessel diameter and flicker response: a 1.5-year follow-up.

PURPOSE: The study examined the influence of individual blood pressure changes overtime on retinal vessel diameter and the latter's response to flicker light. METHODS: The diameter of a retinal arterial and venous segment was measured continuously on-line with a Dynamic Vessel Analyzer in 20 patients twice (mean interval between examinations of 24 months). Eleven patients had no cardiovascular disease. Nine patients had arterial hypertension and were untreated at the time of the first measurement; at the time of the second measurement they were undergoing various antihypertensive therapies. Each test consisted of a 50-s baseline plus three 20-s periods of flicker stimulation followed by an 80-s period of observation. During the examinations the blood pressure was measured at 1-minute intervals. RESULTS: In the hypertension group changes in the mean arterial blood pressure (MAP) correlated significantly with changes in the arterial baseline diameter (y = -0.1 - 0.37x, r =0.74, p (increase) <0.03). A comparison of the two measurements showed no such relationship in the group of cardiovascularly healthy subjects. The venous baseline and the arterial and venous flicker response did not change significantly in either group between the two measurements and showed no relationship to blood pressure changes. CONCLUSIONS: In hypertensive subjects, long-term therapy-related changes in blood pressure induced a change in the arterial baseline by approximately +3.7 microm/-10 mmHg MAP. An influence of lowering MAP to the arterial flicker response could not be detected.

[Variance of retinal vessel diameter response to flicker light. A methodical clinical study]. / Varianz der Netzhautgefässreaktion auf Flickerlicht. Eine klinisch-methodische Studie.

AIM: The study investigated the variance of the retinal vessel response to flicker light between the right and left eyes and after a short and a medium-length time interval. METHODS: The prospective study included 28 volunteers. In the first exam both eyes were examined. One eye selected randomly was measured again after 1 h and after 1 month. The diameter response of an arterial and venous vessel segment was measured continuously by a Dynamic Vessel Analyzer (DVA, IMEDOS, Jena). Each examination consisted of 50 s baseline measurement and three periods of 20-s flicker light provocation followed by 80 s observation. The mean of three provocational cycles was calculated as dynamic vessel response. RESULTS: A significant correlation of the flicker response parameters between the right and left eyes was found. Arterial and venous baseline diameter, flicker light dilation, AVDQ, and BP did not change significantly between the first and follow-up examinations. There was no correlation between changes of BP and changes of vessel diameter parameters in the follow-up exams. CONCLUSION: Flicker-evoked dilation of retinal arterioles measured by the DVA is characterized under similar conditions by small variance after short and medium-length time periods. Therefore, this parameter is suitable as a functional parameter of the regulation ability of retinal arteries.

Focal extracellular potential: a means to monitor electrical activity in single cardiac myocytes.

The focal extracellular potential (FEP) described in this study is an electrophysiological signal related to the transmembrane potential (V(m)) of cardiac myocytes that avoids the mechanical fragility, interference with contraction, and intracellular contact associated with conventional whole cell recording. One end of a frog ventricular myocyte was secured into a glass holding pipette. The FEP was measured differentially between this pipette and a bath pipette while the cell was voltage- or current-clamped by a third whole cell pipette. The FEP appeared as an amplitude-truncated action potential, while FEP duration accurately reflected the action potential duration (APD) at 90% repolarization (APD(90)). FEP magnitude increased as the holding pipette K(+) concentration ([K(+)]) was increased. The FEP-voltage relation was quasi-linear at negative V(m) with a slope that increased with elevated holding pipette [K(+)]. Increasing the membrane conductance inside the holding pipette by adding amphotericin B or cromakalim linearized the FEP-voltage relation across all V(m). The FEP accurately reported electrical activation and APD(90) during changes of stimulation frequency and episodes of cellular stretch.

H2O/OH ratio determination in hydrous aluminosilicate glasses by static proton NMR and the effect of chemical shift anisotropy.

Static 1H NMR spectra of hydrous NaAlSi3O8 glasses have been acquired at low temperature (140 K) in order to quantitatively determine OH and H2O concentrations. Since both components overlap in the spectra, an unambiguous determination of the line shapes is required. The structurally bonded hydroxyl groups are well described by a Gaussian line and the water molecules exhibit a Pake doublet-like line shape due to the strong proton-proton dipolar interaction. However, at proton resonance frequencies used in this study (360 MHz), the Pake doublet has an asymmetric line shape due to chemical shift anisotropy (CSA), which is significant and must be included in any simulation in order to reproduce the experimental line shape successfully. The simulations for rigid water molecules dissolved in our hydrous aluminosilicate glasses result in a CSA of 30+/-5 ppm and a dipolar interaction constant of 63.8+/-2.5 kHz (i.e., dipolar coupling constant (DCC) of 42.6+/-1.7 kHz), corresponding to a proton-proton distance of r(ij) = 154+/-2 pm. In contrast to earlier work, water speciation obtained from the simulations of our 1H NMR spectra are in excellent agreement with those obtained from infrared (IR) spectroscopy.