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In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole.

We model the ultraviolet spectra of the Seyfert 1 galaxy NGC 5548 obtained with the Hubble Space Telescope during the 6 month reverberation mapping campaign in 2014. Our model of the emission from NGC 5548 corrects for overlying absorption and deblends the individual emission lines. Using the modeled spectra, we measure the response to continuum variations for the deblended and absorption-corrected individual broad emission lines, the velocity-dependent profiles of Ly and C iv, and the narrow and broad intrinsic absorption features. We find that the time lags for the corrected emission lines are comparable to those for the original data. The velocity-binned lag profiles of Ly and C iv have a double-peaked structure indicative of a truncated Keplerian disk. The narrow absorption lines show a delayed response to continuum variations corresponding to recombination in gas with a density of ∼105 cm-3. The high-ionization narrow absorption lines decorrelate from continuum variations during the same period as the broad emission lines. Analyzing the response of these absorption lines during this period shows that the ionizing flux is diminished in strength relative to the far-ultraviolet continuum. The broad absorption lines associated with the X-ray obscurer decrease in strength during this same time interval. The appearance of X-ray obscuration in ∼2012 corresponds with an increase in the luminosity of NGC 5548 following an extended low state. We suggest that the obscurer is a disk wind triggered by the brightening of NGC 5548 following the decrease in size of the broad-line region during the preceding low-luminosity state.

During the Space Telescope and Optical Reverberation Mapping Project observations of NGC 5548, the continuum and emission-line variability became decorrelated during the second half of the six-month-long observing campaign. Here we present Swift and Chandra X-ray spectra of NGC 5548 obtained as part of the campaign. The Swift spectra show that excess flux (relative to a power-law continuum) in the soft X-ray band appears before the start of the anomalous emission-line behavior, peaks during the period of the anomaly, and then declines. This is a model-independent result suggesting that the soft excess is related to the anomaly. We divide the Swift data into on- and off-anomaly spectra to characterize the soft excess via spectral fitting. The cause of the spectral differences is likely due to a change in the intrinsic spectrum rather than to variable obscuration or partial covering. The Chandra spectra have lower signal-to-noise ratios, but are consistent with the Swift data. Our preferred model of the soft excess is emission from an optically thick, warm Comptonizing corona, the effective optical depth of which increases during the anomaly. This model simultaneously explains all three observations: the UV emission-line flux decrease, the soft-excess increase, and the emission-line anomaly.

We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 +-optical continuum by 4.17+0.36-0.36 and 0.79+0.35-0.34 days, respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Lyα, He ii(+O iii]), and Si iv(+O iv]) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the R BLR-L AGN relation based on the past behavior of NGC 5548.

We conduct a multiwavelength continuum variability study of the Seyfert 1 galaxy NGC 5548 to investigate the temperature structure of its accretion disk. The 19 overlapping continuum light curves (1158 A oto 9157 A o) combine simultaneous Hubble Space Telescope, Swift, and ground-based observations over a 180 day period from 2014 January to July. Light-curve variability is interpreted as the reverberation response of the accretion disk to irradiation by a central time-varying point source. Our model yields the disk inclination i = 36° ±10° temperature T1 = 44 ±6 ) × 10 3 K at 1 light day from the black hole, and a temperatureradius slope (T ∞r-a) of a = 0.99 ±0.03. We also infer the driving light curve and find that it correlates poorly with both the hard and soft X-ray light curves, suggesting that the X-rays alone may not drive the ultraviolet and optical variability over the observing period. We also decompose the light curves into bright, faint, and mean accretion-disk spectra. These spectra lie below that expected for a standard blackbody accretion disk accreting at L LEdd = 0.1.

During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert 1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far UV continuum and broad emission line variations decorrelated for ∼60-70 days, starting ∼75 days after the first HST/COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterized by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission line flux deficits occurred for the high ionization, collisionally excited lines C iv and Si iv(+O iv]), and also He ii(+O iii]), while the anomaly in Lywas substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon broad line region (BLR) clouds by a moving veil of material lying between the inner accretion disk and inner (BLR), perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies >54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation.

We present ground-based optical photometric monitoring data for NGC 5548, part of an extended multiwavelength reverberation mapping campaign. The light curves have nearly daily cadence from 2014 January to July in nine filters (BVRI and ugriz). Combined with ultraviolet data from the Hubble Space Telescope and Swift, we confirm significant time delays between the continuum bands as a function of wavelength, extending the wavelength coverage from 1158 Å to the z band (∼9160 Å). We find that the lags at wavelengths longer than the V band are equal to or greater than the lags of high-ionization-state emission lines (such as He ii and λ1640 and λ4686), suggesting that the continuum-emitting source is of a physical size comparable to the inner broad-line region (BLR). The trend of lag with wavelength is broadly consistent with the prediction for continuum reprocessing by an accretion disk with τ ∝ λ 4 . However, the lags also imply a disk radius that is 3 times larger than the prediction from standard thin-disk theory, assuming that the bolometric luminosity is 10% of the Eddington luminosity (L = 0.1 L Edd ). Using optical spectra from the Large Binocular Telescope, we estimate the bias of the interband continuum lags due to BLR emission observed in the filters. We find that the bias for filters with high levels of BLR contamination (∼20%) can be important for the shortest continuum lags and likely has a significant impact on the u and U bands owing to Balmer continuum emission.

We present ultraviolet (UV) observations of six nearby Type Ia supernovae (SNe Ia) obtained with the Hubble Space Telescope, three of which were also observed in the near-IR (NIR) with Wide-Field Camera 3. UV observations with the Swift satellite, as well as ground-based optical and NIR data provide complementary information. The combined data set covers the wavelength range 0.2-2 μm. By also including archival data of SN 2014J, we analyse a sample spanning observed colour excesses up to E(B - V) = 1.4 mag. We study the wavelength-dependent extinction of each individual SN and find a diversity of reddening laws when characterized by the total-to-selective extinction RV. In particular, we note that for the two SNe with E(B - V) ≳ 1 mag, for which the colour excess is dominated by dust extinction, we find RV = 1.4 ± 0.1 and RV = 2.8 ± 0.1. Adding UV photometry reduces the uncertainty of fitted RV by ~50 per cent allowing us to also measure RV of individual low-extinction objects which point to a similar diversity, currently not accounted for in the analyses when SNe Ia are used for studying the expansion history of the Universe.

Optimisation of energy efficiency and operational performance as well as assessment of safety levels and emissions of marine operations require detailed information about the acting wave system. It is possible-with an analogy to classical wave buoys-to estimate the directional wave spectrum by processing sensor measurements of wave-induced responses (e.g., motions and structural responses) from a ship. Compared to other sources of wave data (e.g., buoys, satellites, third-generation wave models), estimation concepts using the ship itself as a buoy provide the wave spectrum at the exact spatio-temporal point, potentially increasing accuracy and with minimal associated cost. This paper gives an overview of the technology, discusses associated uncertainties, and highlights new developments made for estimating waves via measured ship responses., (© 2023. Springer Nature Limited.)

Aim: The aim of this retrospective observational study was to determine how response intervals correlated to the experience of the community first responders (CFRs) using data collected from the Danish Island of Langeland via a global positioning system (GPS)-based system., Methods: All medical emergency calls involving CFRs in the time period from 21st of April 2012 to 31st of December 2017 were included. Each emergency call activated 3 CFRs. Response intervals were calculated using the time from when the system alerted the CFRs to CFR time of arrival at the emergency site measured by GPS. CFRs response intervals were grouped depending on their level of experience according to ≤ 10, 11-24, 25-49, 50-99, ≥ 100 calls accepted and arrived on-site., Results: A total of 7273 CFR activations were included. Median response interval for the CFR arriving first on-site (n = 3004) was 4:05 min (IQR 2:42-6:01) and median response interval for the arrival of the CFR with an automated external defibrillator (n = 2594) was 5:46 min (IQR 3:59-8:05). Median response intervals were 5:53 min (3:43-8:29) for ≤ 10 calls (n = 1657), 5:39 min (3:49-8:01) for 11-24 calls (n = 1396), 5:45 min (3:49-8:00) for 25-49 calls (n = 1586), 5:07 min (3:38-7:26) for 50-99 calls (n = 1548) and 4:46 min (3:14-7:32) for ≥ 100 calls (n = 1086) (p < 0.001). There was a significant negative correlation between experience and response intervals (p < 0.001, Spearman's rho = -0.0914)., Conclusion: This study found an inverse correlation between CFR experience and response intervals, which could lead to increased survival after a time-critical incident., (© 2023. The Author(s).)

Analysis of international public-sector contributions to Food and Drug Administration (FDA)-approved drugs and vaccines allows for a more thorough examination of the global biomedical innovation ecosystem by institution of origin. Using new and existing methods, we have identified 364 FDA-approved drugs and vaccines approved from 1973 to 2016 discovered in whole or in part by Public Sector Research Institutions (PSRIs) worldwide. We identified product-specific intellectual property contributions to FDA-approved small molecule and biologic drugs and vaccines from the FDA Orange Book, our peer network, published studies, and three new sources: reports of medical product manufacturers' payments to physicians and teaching hospitals under The Sunshine Act of 2010, a paper by Kneller and 64 royalty monetization transactions by academic institutions and/or their faculty that one of us (AS) maintains. We include a total of 293 drugs discovered either wholly by a US PSRI or jointly by a U.S. and a non-U.S. PSRI. 119 FDA-approved drugs and vaccines were discovered by PSRIs outside the U.S. Of these, 71 were solely discovered outside the US, while 48 also involved intellectual property contributions by US PSRIs. In the context of the global public sector landscape, the US dominates drug discovery, accounting for two-thirds of these drugs and many of the important, innovative vaccines introduced over the past 30 years. Contributions by Canada, UK, Germany, Belgium, Japan, and others each amount to 5.4% or less of the total., Supplementary Information: The online version contains supplementary material available at 10.1007/s10961-023-10007-z., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© The Author(s) 2023.)

Background/objective: Emerging adulthood (EA, age range between 18 to 29 years) is an important developmental stage that is characterized by marked social and psychological changes. Currently, its developmental features are quantified by the Inventory of the Dimensions of Emerging Adulthood (IDEA) but a validated Chinese version of this questionnaire (IDEA-C) is lacking. Thus, this research, which consists of two consecutive studies, aimed to investigate the psychometric properties of the translated IDEA in a Chinese sample of emerging adults., Method: Firstly, a forward-backward translation of the IDEA-C scale was conducted. Item analysis and exploratory factor analysis were performed in Sample 1a ( n  = 2438), followed by structural validity test in Sample 1b ( n  = 2461). Concurrent validity and internal consistency were evaluated in Sample 1( n  = 4899). Finally, test-retest reliability was tested in Sample 2 ( n  = 185). Then, the second study aimed to test the factor structure proposed by study 1 in the non-student sample ( n  = 2200) by confirmatory factor analysis. In addition, the second study also investigated whether the attainment of college education influenced the EA experience of non-student emerging adults in China. And the association was examined between the socioeconomic status of emerging adults and the subscales of IDEA., Results: In the college sample, the IDEA-C scale presented a four-factor structure different from the original five-factor structure (χ2(190)=1116.84, p  < 0.001; CFI = 0.97; TLI = 0.96; SRMR = 0.039; RMSEA = 0.050 [90%CI=0.047-0.052]). In addition, IDEA-C exhibited good internal consistency reliability (Cronbach's alpha >0.77), test-retest reliability (r>0.49, p  < 0.01) and concurrent validity. And the CFA in non-student sample also showed an adequate fit indices (χ2(158) =710.10, p  < 0.001, TLI=0.93, CFI=0.94, SRMR=0.038, RMSEA=0.04 [90%CI=0.037-0.040]) and an adequate internal consistency (Cronbach's alpha >0.64) and test-retest reliability (r>0.43, p  < 0.01)., Conclusion: The results of the present study confirmed that the Chinese version of the IDEA is found to be valid for measuring psychological characteristics of EA in Chinese-speaking samples of emerging adults., (© 2022 The Author(s).)

Background: Delirium is one of the most common complications among elderly hospitalized patients, postoperative patients and patients on intensive care units with a prevalence between 11 and 80%. Delirium is associated with higher morbidity and mortality. Reliable instruments are required to detect delirium at an early time point. The Nursing-Delirium Screening Scale (Nu-DESC) is a screening tool with high sensitivity and good specificity. However, there is currently no official translation after ISPOR guidelines of any Danish delirium assessment tools available. Thereby hampering the implementation of 2017 ESA-Guidelines on postoperative Delirium in the clinical routine. The aim of this study is to provide an official translation and evaluation of the Nu-DESC into Danish following the ISPOR process., Methods: The Nu-DESC was translated after International Society for Pharmacoecomonics and Outcome Research (ISPOR) guidelines to Danish after permission of the original author, and is evaluated by medical staff and finally approved by the original author., Results: All steps of the ISPOR guideline were consecutively followed, without any major problems. The evaluation of the Nu-DESC DK regarding its intelligibility and feasibility showed no statistically significant differences between nurses and medical doctors ratings. The translation was authorized and approved by the original author., Conclusion: This study provides the Nu-DESC DK, an official Danish delirium screening instrument, which can detect all psychomotor types of delirium., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Type IV pili are widely expressed among Gram-negative bacteria, where they are involved in biofilm formation, serve in the transfer of DNA, motility and in the bacterial attachment to various surfaces. Type IV pili in Shewanella oneidensis are also supposed to play an important role in extracellular electron transfer by the attachment to sediments containing electron acceptors and potentially forming conductive nanowires., Results: The potential nanowire type IV pilin PilBac1 from S. oneidensis was characterized by a combination of complementary structural methods and the atomic structure was determined at a resolution of 1.67 Å by X-ray crystallography. PilBac1 consists of one long N-terminal α-helix packed against four antiparallel β-strands, thus revealing the core fold of type IV pilins. In the crystal, PilBac1 forms a parallel dimer with a sodium ion bound to one of the monomers. Interestingly, our PilBac1 crystal structure reveals two unusual features compared to other type IVa pilins: an unusual position of the disulfide bridge and a straight α-helical section, which usually exhibits a pronounced kink. This straight helix leads to a distinct packing in a filament model of PilBac1 based on an EM model of a Neisseria pilus., Conclusions: In this study we have described the first structure of a pilin from Shewanella oneidensis. The structure possesses features of the common type IV pilin core, but also exhibits significant variations in the α-helical part and the D-region.

In this commentary on the article by Trzesniewski and Donnellan (2010, this issue), I focus on the question of why young people today are viewed so negatively, despite the lack of evidence that they are worse (or worse off) now than they were in decades past. I propose that an important reason is the rise of emerging adulthood as a new life stage in between adolescence and young adulthood. Emerging adulthood developed in part because young people enter adult roles of stable work, marriage, and parenthood later now than they did in the past, leading many older people to view them as "late" or selfish, and the new features of this new life stage are frequently misunderstood and misinterpreted. I emphasize that the rise emerging adulthood is not merely generational but is likely to be a permanent addition to the life course., (© The Author(s) 2010.)

Purpose: We did a phase I dose-escalation trial to evaluate the feasibility and safety of intratumoral injections of C Cure 709, an allogeneic, continuous CTL cell line that, restricted by HLA-A2, recognizes MART-1-positive tumor cells through transduction with a T-cell receptor encoding gene., Experimental Design: Cells were administered intratumorally in four dose levels ranging from 10(8) to 10(9) cells/d on days 1, 4, 7, 10, 14, and 28 of each treatment cycle to patients with metastatic melanoma. Main inclusion criteria were HLA-A2 tissue type, MART-1-positive tumor cells, and metastases suitable for ultrasound-guided injections. Patients were assessed for toxicity and response. Three to six patients were treated per dose level. Patients without progressive disease were offered up to three treatment cycles., Results: Fifteen patients received a total of 24 treatment cycles with a total of 266 injections of C Cure 709. Toxicity was minor to moderate and most common injection site reactions were fever, fatigue, nausea/vomiting, and arthralgia/myalgia. Side effects disappeared in general within 24 hours. Toxicity was not dose dependent. One patient obtained a partial response, encompassing both metastases used and not used for intratumoral injections. Remaining patients did not achieve an overall response. In addition, we observed local regression of metastases used for injection in two patients and of metastases not used for injection in one patient., Conclusion: Intratumoral injections of C Cure 709 are feasible, safe, and capable of inducing tumor regression. Further investigation in a phase II setting is warranted.

Purpose: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma., Experimental Design: Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry., Results: At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4(+), CD8(+), CD56(+), and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4(+), CD8(+), and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level., Conclusion: These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2-based immunotherapy.

The aim of the present study was to analyse lymphocyte subsets in consecutive peripheral blood samples and consecutive tumour tissue core needle biopsies performed before and during interleukin-2 based immunotherapy, and to correlate the findings with objective response and survival. Twenty-six patients with metastatic renal cell carcinoma were treated with low dose s.c. interleukin-2, interferon-alpha and histamine. A total of 250 blood samples and 62 core needle biopsies from 23 and 19 of these patients, respectively, were analysed. After 2 weeks of treatment, a significant positive correlation between absolute number of peripheral blood lymphocytes (P=0.028), CD3 (P=0.017), CD57 (P=0.041) and objective response was demonstrated. There was no correlation between any peripheral blood leukocyte subsets and survival. Cytotoxicity of peripheral blood mononuclear cells was not correlated to objective response or survival. Within the tumour tissue at baseline, a significant positive correlation between CD4 (P=0.027), CD8 (P=0.028), CD57 (P=0.007) and objective response was demonstrated. After one month of immunotherapy, a significant positive correlation between intratumoral CD3 (P=0.026), CD8 (P=0.015), CD57 (P=0.009) and objective response was demonstrated. A significant positive correlation between intratumoral baseline CD4 (P=0.047), baseline CD57 (P=0.035), CD3 at one month (P=0.049) and survival was demonstrated. These data provide novel in vivo evidence of the possible contribution of lymphocyte subsets in the tumour reduction in responding patients during interleukin-2 based immunotherapy. Confirmation of the results requires further studies including a larger number of patients.

Jack-up platforms are sensitive to dynamic amplification in waves because their fundamental period can be as high as 7 s-8 s. Where as the dynamic motion of the platforms is rather well described by linear theory the excitation depends nonlinearly on the wave height. The stochastic wave loading is thus far from being normally distributed. In this paper dynamic amplifications obtained by the diffusion theory extended to cover nonnormal excitations are compared with available time simulation results in irregular seaways. Generally, the time simulations seem to yield responses less nonlinear in the wave heights than the responses estimated from the diffusion theory. Explanations for these discrepancies are discussed and mainly attributed to a proper choice of total damping.

Oral administration of 1 g of acetazolamide to 8 normal subjects studied at sea level and in normoxia caused an acute increase in cerebral blood flow (CBF). During the subsequent prolonged oral treatment with 1 g of acetazolamide daily, CBF returned to normal within 2 days. The alveolar CO2 tension decreased gradually to 70% of the control value, indicating hyperventilation. At sea level hyperventilation will not increase brain oxygenation significantly in normal man, as the arterial oxygen content only increases minimally, while CBF is unchanged. At high altitude the beneficial effects of acetazolamide on the symptoms of acute mountain sickness may well be due to an improved oxygen supply to the brain, as hyperventilation will, at the low ambient PO2, cause a significant increase of the arterial oxygen content, while CBF presumably is unaffected by the drug. During hypoxia at high altitude the overall effect of prolonged acetazolamide treatment may thus be equivalent to a descent by several hundred metres.