Note on dose conversion for radon exposure.

The epidemiological approach to converting radon exposure to effective dose is examined. Based on the definition of the effective dose, the dose conversion is obtained from the equivalence of lung-specific detriment associated with low-LET radiation and with radon exposure. This approach most reliably estimates effective dose per radon exposure on the basis of epidemiological data and implicitly includes the radiation weighting factor required to calculate the effective dose from radon exposure using the dosimetric approach, applying biokinetic and dosimetric models. Consistency between the results of the epidemiological and dosimetric approaches is achieved by using a radiation weighting factor of about 10 for alpha particles instead of the current ICRP value of 20. In contrast, the epidemiological approach implemented in ICRP 65, and referred to as dose conversion convention, was based on direct comparison of total radiation detriment with lung detriment from radon exposure. With the revision of radiation detriments in ICRP 103, this approach can be judged to overestimate the effective dose per radon exposure by about a factor of two because the tissue weighting factor for lung differs from the value of relative detriment to which it relates.

Three distinct patterns of mental health response following accidents in mountain sports: a follow-up study of individuals treated at a tertiary trauma center.

The restorative effect of physical activity in alpine environments on mental and physical health is well recognized. However, a risk of accidents and post-accident mental health problems is inherent to every sport. We aimed to characterize mental health in individuals following mountain sport accidents requiring professional medical management. Adult victims of mountain sport accidents treated at the hospital of the Medical University of Innsbruck (Austria) between 2018 and 2020 completed a cross-sectional survey at least 6 months following the admission (median 44 months, n = 307). Symptoms of post-traumatic stress disorder (PTSD, PCL-5), anxiety, depression, and somatization (PHQ), resilience (RS-13), sense of coherence (SOC-9L), post-traumatic growth (PTGI), and quality of life (EUROHIS-QOL), as well as sociodemographic and clinical information, were obtained from an online survey and extracted from electronic health records. Mental health outcome patterns were investigated by semi-supervised medoid clustering and modeled by machine learning. Symptoms of PTSD were observed in 19% of participants. Three comparably sized subsets of participants were identified: a (1) neutral, (2) post-traumatic growth, and (3) post-traumatic stress cluster. The post-traumatic stress cluster was characterized by high prevalence of symptoms of mental disorders, low resilience, low sense of coherence, and low quality of life as well as by younger age, the highest frequency of pre-existing mental disorders, and persisting physical health consequences of the accident. Individuals in this cluster self-reported a need for psychological or psychiatric support following the accident and more cautious behavior during mountain sports since the accident. Reliability of machine learning-based prediction of the cluster assignment based on 40 variables available during acute medical treatment of accident victims was limited. A subset of individuals show symptoms of mental health disorders including symptoms of PTSD when assessed at least 6 months after mountain sport accident. Since early identification of these vulnerable patients remains challenging, psychoeducational measures for all patients and low-threshold access to mental health support are key for a successful interdisciplinary management of victims of mountain sport accidents.

Structural biology in the age of X-ray free-electron lasers and exascale computing.

Serial femtosecond X-ray crystallography has emerged as a powerful method for investigating biomolecular structure and dynamics. With the new generation of X-ray free-electron lasers, which generate ultrabright X-ray pulses at megahertz repetition rates, we can now rapidly probe ultrafast conformational changes and charge movement in biomolecules. Over the last year, another innovation has been the deployment of Frontier, the world's first exascale supercomputer. Synergizing extremely high repetition rate X-ray light sources and exascale computing has the potential to accelerate discovery in biomolecular sciences. Here we outline our perspective on each of these remarkable innovations individually, and the opportunities and challenges in yoking them within an integrated research infrastructure.

Characteristics associated with patient-reported treatment success in psoriatic arthritis.

OBJECTIVES: To determine characteristics associated with patient-reported treatment success in psoriatic arthritis (PsA). METHODS: Rheumatologist-diagnosed PsA patients fulfilling the CASPAR classification were recruited from a single center. PsA outcome measures included: 66/68 swollen/tender joint counts, Leeds/SPARCC dactylitis/enthesitis indices, psoriasis body surface area (BSA), and patient-reported outcomes (PROs) including PROMIS. The primary outcome was a patient-reported item: "Today, considering the level of control of your psoriatic arthritis and psoriasis, do you consider your treatment has been successful?" Descriptive and multivariate logistic regression analyses identified clinical predictors of patient-reported treatment success. Patient-reported reasons for lack of treatment success were explored. RESULTS: A total of 178 participants had a baseline visit. Mean (SD) CASPAR score was 3.7 (0.9), age 51.7 (13.5) years, and BMI 31.3 (7.2) kg/m2. Fifty-two percent were women, and 86.0% white. Treatment success was reported by 116/178(65%) patients in the analytic cohort. Among 76 patients who reported treatment failure, the most frequently selected reasons for lack of success were pain (n = 55, 72.4%), fatigue (n = 46, 60.5%), inflamed joints (n = 40, 52.6%), and stiffness (n = 40, 52.6%). Overall, 105 participants had complete data across variables in the logistic regression models. Patient-reported treatment success was independently associated with the 66-swollen/68-tender joint counts, psoriasis BSA, PROs (pain interference, physical function, fatigue), and TNF-inhibitor therapy, after controlling for BMI and demographics. CONCLUSION: Patient-reported treatment success in PsA may be achieved through improvement of inflammatory arthritis, psoriasis, pain, physical function, fatigue, and the use ofTNF-inhibitors. Patients reported treatment failure was most commonly due to symptoms of pain, fatigue and stiffness.

All-Atom Biomolecular Simulation in the Exascale Era.

Exascale supercomputers have opened the door to dynamic simulations, facilitated by AI/ML techniques, that model biomolecular motions over unprecedented length and time scales. This new capability holds the potential to revolutionize our understanding of fundamental biological processes. Here we report on some of the major advances that were discussed at a recent CECAM workshop in Pisa, Italy, on the topic with a primary focus on atomic-level simulations. First, we highlight examples of current large-scale biomolecular simulations and the future possibilities enabled by crossing the exascale threshold. Next, we discuss challenges to be overcome in optimizing the usage of these powerful resources. Finally, we close by listing several grand challenge problems that could be investigated with this new computer architecture.

MD Simulation of Water Using a Rigid Body Description Requires a Small Time Step to Ensure Equipartition.

In simulations of aqueous systems, it is common to freeze the bond vibration and angle bending modes in water to allow for a longer time step δt for integrating the equations of motion. Thus, δt = 2 fs is often used in simulating rigid models of water. We simulate the SPC/E model of water using δt from 0.5 to 3.0 fs and up to 4 fs using hydrogen mass repartitioning. In these simulations, we find that for all but δt = 0.5 fs, equipartition is not obtained between translational and rotational modes, with the rotational modes exhibiting a lower temperature than the translation modes. To probe the reasons for the lack of equipartition, we study the autocorrelation of the translational velocity of the center of mass and the angular velocity of the rigid water molecule, respectively. We find that the rotational relaxation occurs on a timescale comparable to vibrational periods, calling into question the original motivations for freezing the vibrations. Furthermore, a time step with δt ≥ 1 fs is not able to capture accurately the fast rotational relaxation, which reveals its impact as an effective slowing-down of rotational relaxation. The fluctuation-dissipation relation then leads to the conclusion that the rotational temperature should be cooler for δt greater than the reference value of 0.5 fs. Consideration of fluctuation-dissipation in equilibrium molecular dynamics simulations also emphasizes the need to capture the temporal evolution of fluctuations with fidelity and the role of δt in this regard. The time step also influences the solution thermodynamic properties: both the mean system potential energies and the excess entropy of hydration of a soft repulsive cavity are sensitive to δt.

Validity of 16 AHRQ Patient Safety Indicators to identify in-hospital complications: a medical record review across nine Swiss hospitals.

The validity of the Agency for Healthcare Research and Quality's Patient Safety Indicators (PSIs) has been established in the USA and Canada. However, these indicators are also used for hospital benchmarking and cross-country comparisons in other nations with different health-care settings and coding systems as well as missing present on admission (POA) flags in the administrative data. This study sought to comprehensively assess and compare the validity of 16 PSIs in Switzerland, where they have not been previously applied. We performed a medical record review using administrative and electronic medical record data from nine Swiss hospitals. Seven independent reviewers evaluated 1245 cases at various hospitals using retrospective data from the years 2014-18. True positives, false positives, positive predictive values (PPVs), and reasons for misclassification were compared across all investigated PSIs, and the documentation quality of the PSIs was examined. PSIs 6 (iatrogenic pneumothorax), 10 (postoperative acute kidney injury), 11 (postoperative respiratory failure), 13 (postoperative sepsis), 14 (wound dehiscence), 17 (birth trauma), and 18 and 19 (obstetric trauma with or without instrument) showed high PPVs (range: 90-99%) and were not strongly influenced by missing POA information. In contrast, PSIs 3 (pressure ulcer), 5 (retained surgical item), 7 (central venous catheter-related bloodstream infection), 8 (fall with hip fracture), and 15 (accidental puncture/laceration) showed low PPVs (range: 18-49%). In the case of PSIs 3, 8, and 12 (perioperative embolism/thrombosis), the low PPVs were largely due to the lack of POA information. Additionally, it was found that the documentation of PSI 3 in discharge letters could be improved. We found large differences in validity across the 16 PSIs in Switzerland. These results can guide policymakers in Switzerland and comparable health-care systems in selecting and prioritizing suitable PSIs for quality initiatives. Furthermore, the national introduction of a POA flag would allow for the inclusion of additional PSIs in quality monitoring.

Creatine Kinase Equilibration and ΔGATP over an Extended Range of Physiological Conditions: Implications for Cellular Energetics, Signaling, and Muscle Performance.

In this report, we establish a straightforward method for estimating the equilibrium constant for the creatine kinase reaction (CK Keq″) over wide but physiologically and experimentally relevant ranges of pH, Mg2+ and temperature. Our empirical formula for CK Keq″ is based on experimental measurements. It can be used to estimate [ADP] when [ADP] is below the resolution of experimental measurements, a typical situation because [ADP] is on the order of micromolar concentrations in living cells and may be much lower in many in vitro experiments. Accurate prediction of [ADP] is essential for in vivo studies of cellular energetics and metabolism and for in vitro studies of ATP-dependent enzyme function under near-physiological conditions. With [ADP], we were able to obtain improved estimates of ΔGATP, necessitating the reinvestigation of previously reported ADP- and ΔGATP-dependent processes. Application to actomyosin force generation in muscle provides support for the hypothesis that, when [Pi] varies and pH is not altered, the maximum Ca2+-activated isometric force depends on ΔGATP in both living and permeabilized muscle preparations. Further analysis of the pH studies introduces a novel hypothesis around the role of submicromolar ADP in force generation.

A novel inclusion complex of oxybenzone with C-methylresorcin[4]arene deters skin permeation.

Oxybenzone (OXB), a very widely used sunscreen ingredient has the potential to block both UVA and UVB but can penetrate through skin. Studies have revealed its presence in the blood and urine of most humans, which may lead to long-term health effects. As the confined cavities of macrocycles can alter the physical and chemical properties of encapsulated guests, in this study, we investigated the formation of host-guest complexes between C-methylresorcin[4]arene and OXB. Combined experimental (NMR spectroscopy, UV/vis absorption, and fluorescence spectroscopy) and theoretical investigation confirmed the formation of a weak host-guest complex that had a 1 : 1 stoichiometry. Furthermore, skin permeation testing revealed that complexation by C-methylresorcin[4]arene significantly reduced the skin permeation of OXB which can potentially limit the harmful effects of this organic sunscreen.

Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

Predominant myosin superrelaxed state in canine myocardium with naturally occurring dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced contractility and ejection fraction. As the identification of its underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether the molecular motor myosin and its known relaxed conformational states are altered in DCM. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six nonfailing (NF) controls. We then used a combination of Mant-ATP chase experiments and X-ray diffraction to assess both energetic and structural changes of myosin. Using the Mant-ATP chase protocol, we observed that in DCM dogs, the amount of myosin molecules in the ATP-conserving conformational state, also known as superrelaxed (SRX), is significantly increased when compared with NF dogs. This alteration can be rescued by applying EMD-57033, a small molecule activating myosin. Conversely, with X-ray diffraction, we found that in DCM dogs, there is a higher proportion of myosin heads in the vicinity of actin when compared with NF dogs (1,0 to 1,1 intensity ratio). Hence, we observed an uncoupling between energetic (Mant-ATP chase) and structural (X-ray diffraction) data. Taken together, these results may indicate that in the heart of Doberman Pinschers with DCM, myosin molecules are potentially stuck in a nonsequestered but ATP-conserving SRX state, that can be counterbalanced by EMD-57033 demonstrating the potential for a myosin-centered pharmacological treatment of DCM.NEW & NOTEWORTHY The key finding of the present study is that, in left ventricles of dogs with a naturally occurring dilated cardiomyopathy, relaxed myosin molecules favor a nonsequestered superrelaxed state potentially impairing sarcomeric contractility. This alteration is rescuable by applying a small molecule activating myosin known as EMD-57033.

Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption.

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.

A Contemporary Review of the Treatment of Medullary Thyroid Carcinoma in the Era of New Drug Therapies.

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that can be sporadic or inherited and is often associated with mutations in the RET (Rearranged during Transfection) oncogene. The primary treatment for MTC is surgical resection of all suspected disease, but recent advances in targeted therapies for MTC, including the selective RET inhibitors selpercatinib and pralsetinib, have led to changes in the management of patients with locally advanced, metastatic, or recurrent MTC. In this article, we review updates on the evaluation and management of patients with MTC, focusing on new and emerging therapies that are likely to improve patient outcomes.

AMPK activation by metformin protects against pulmonary hypertension in rats and relaxes isolated human pulmonary artery.

Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI2) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats.

Healthcare Costs and Health-Related Quality of Life in Older Multimorbid Patients After Hospitalization.

Objectives: We identified factors associated with healthcare costs and health-related quality of life (HRQoL) of multimorbid older adults with polypharmacy. Methods: Using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid older people) trial, we described the magnitude and composition of healthcare costs, and time trends of HRQoL, during 1-year after an acute-care hospitalization. We performed a cluster analysis to identify groups with different cost and HRQoL trends. Using multilevel models, we also identified factors associated with costs and HRQoL. Results: Two months after hospitalization monthly mean costs peaked (CHF 7'124) and HRQoL was highest (0.67). They both decreased thereafter. Age, falls, and comorbidities were associated with higher 1-year costs. Being female and housebound were negatively associated with HRQoL, while moderate alcohol consumption had a positive association. Being independent in daily activities was associated with lower costs and higher HRQoL. Conclusion: Although only some identified potential influences on costs and HRQoL are modifiable, our observations support the importance of prevention before health deterioration in older people with multimorbid illness and associated polypharmacy.

A comparison of multiband and multiband multiecho gradient-echo EPI for task fMRI at 3 T.

A multiband (MB) echo-planar imaging (EPI) sequence is compared to a multiband multiecho (MBME) EPI protocol to investigate differences in sensitivity for task functional magnetic resonance imaging (fMRI) at 3 T. Multiecho sampling improves sensitivity in areas where single-echo-EPI suffers from dropouts. However, It requires in-plane acceleration to reduce the echo train length, limiting the slice acceleration factor and the temporal and spatial resolution Data were acquired for both protocols in two sessions 24 h apart using an adapted color-word interference Stroop task. Besides protocol comparison statistically, we performed test-retest reliability across sessions for different protocols and denoising methods. We evaluated the sensitivity of two different echo-combination strategies for MBME-EPI. We examined the performance of three different data denoising approaches: "Standard," "AROMA," and "FIX" for MB and MBME, and assessed whether a specific method is preferable. We consider using an appropriate autoregressive model order within the general linear model framework to correct TR differences between the protocols. The comparison between protocols and denoising methods showed at group level significantly higher mean z-scores and the number of active voxels for MBME in the motor, subcortical and medial frontal cortices. When comparing different echo combinations, our results suggest that a contrast-to-noise ratio weighted echo combination improves sensitivity in MBME compared to simple echo-summation. This study indicates that MBME can be a preferred protocol in task fMRI at spatial resolution (≥2 mm), primarily in medial prefrontal and subcortical areas.

Haemoglobin thresholds for transfusion: how are we doing in the era of Choosing Wisely? A retrospective cohort study.

INTRODUCTION:  Clinical practice guidelines and the Choosing Wisely initiative launched in 2012 recommend a haemoglobin (Hb) threshold of 70-80 g/lfor red blood cell (RBC) transfusions in stable hospitalised patients. Data on transfusion practices and their trends in medical inpatients are limited. To address this gap, we investigated transfusion practices and their trends in general internal medicine and other clinics. METHODS: This retrospective cohort study analysed data from all hospitalisations with RBC transfusions at a Swiss university hospital between 2012 and 2019. We included all first transfusion episodes if pretransfusion Hb was available. The primary endpoint was mean pretransfusion Hb; secondary endpoints included potentially inadequate transfusions (i.e., transfusions at Hb ≥80 g/l) and receipt of a single RBC unit. Trends in mean pretransfusion Hb over time were estimated using generalised estimating equations, and risk factors for potentially inadequate transfusions were identified using multivariable adjusted generalised estimating equations models. RESULTS:  Of 14,598 hospitalisations with RBC transfusions, 1980 (13.6%) were discharged from general internal medicine. From 2012 to 2019, mean pretransfusion Hb decreased from 74.0 g/l to 68.8 g/l in general internal medicine (mean annual decrease -0.76 g/l, 95% confidence interval [CI] -0.51 to -1.02) and from 78.2 g/l to 72.7 g/l in other clinics (mean annual decrease -0.69, 95% CI -0.62 to -0.77; p for interaction 0.53). The overall proportion of potentially inadequate transfusions was 17.8% in general internal medicine and 24.1% in other clinics (p <0.001) and decreased over the study period from 26.9% to 5.5% in general internal medicine and from 37.0% to 15.2% in other clinics. In contrast, the proportion of cases receiving a single RBC unit increased (39.5% to 81.4% in general internal medicine, 42.7% to 66.1% in other clinics). Older age (adjusted odds ratio [aOR] 1.45, 95% CI 1.32-1.58 for ≥65 vs <65 years), having surgery (aOR 1.24, 95% CI 1.14-1.36), acute haemorrhage (aOR 1.16, 95% CI 1.02-1.33), chronic heart failure (aOR 1.17, 95% CI 1.04-1.32), ischaemic heart diseases (aOR 1.27, 95% CI 1.15-1.41), chronic pulmonary diseases (aOR 1.24, 95% CI 1.08-1.42), malignancy (aOR 1.11, 95% CI 1.01-1.21), and rheumatic disease (aOR 1.27, 95% CI 1.01-1.59) were risk factors for potentially inadequate transfusions. CONCLUSIONS:  More restrictive transfusion practices were adopted in general internal medicine and other clinics over time, suggesting that guideline recommendations and the Choosing Wisely initiative may have been increasingly followed. Interventions to reduce potentially inadequate transfusions should target providers who care for older patients and those with surgery or chronic cardiac and pulmonary diseases.

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy.

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

Assessment of a host-guest interaction in a bilayer membrane model.

Supramolecular interactions are well recognized and many of them have been extensively studied in chemistry. The formation of supramolecular complexes that rely on weak force interactions are less well studied in bilayer membranes. Herein, a supported bilayer membrane is used to probe the penetration of a complex between tetracycline and a macrocyclic polyether. In a number of bacterial systems, the presence of the macrocycle has been found to significantly enhance the potency of the antimicrobial in vitro. The crown·tetracycline complex has been characterized in solution, neutron reflectometry has probed complex penetration, and the phenomena have been modeled by computational methods.