National coverage of out-of-hospital cardiac arrests using automated external defibrillator-equipped drones - A geographical information system analysis.

BACKGROUND: Early defibrillation is essential for increasing the chance of survival in out-of-hospital-cardiac-arrest (OHCA). Automated external defibrillator (AED)-equipped drones have a substantial potential to shorten times to defibrillation in OHCA patients. However, optimal locations for drone deployment are unknown. Our aims were to find areas of high incidence of OHCA on a national level for placement of AED-drones, and to quantify the number of drones needed to reach 50, 80, 90 and 100% of the target population within eight minutes. METHODS: This is a retrospective observational study of OHCAs reported to the Swedish Registry for Cardiopulmonary Resuscitation between 2010-2018. Spatial analyses of optimal drone placement were performed using geographical information system (GIS)-analyses covering high-incidence areas (>100 OHCAs in 2010-2018) and response times. RESULTS: 39,246 OHCAs were included. To reach all OHCAs in high-incidence areas with AEDs delivered by drone or ambulance within eight minutes, 61 drone systems would be needed, resulting in overall OHCA coverage of 58.2%, and median timesaving of 05:01 (min:sec) [IQR 03:22-06:19]. To reach 50% of the historically reported OHCAs in <8 min, 21 drone systems would be needed; for 80%, 366; for 90%, 784, and for 100%, 2408. CONCLUSIONS: At a national level, GIS-analyses can identify high incidence areas of OHCA and serve as tools to quantify the need of AED-equipped drones. Use of only a small number of drone systems can increase national coverage of OHCA substantially. Prospective real-life studies are needed to evaluate theoretically optimized suggestions for drone placement.

Incidence and characteristics of drowning in Sweden during a 15-year period.

AIM: Drowning is a global health problem and deeper knowledge about the extent and causes is of utmost importance for implementing preventative actions. The aim of this study was to describe the incidence and characteristics of drowning in Sweden over time, including both non-fatal and fatal cases. METHODS: All cases identified as drowning (ICD-10 coding) at a national level in Sweden between 2003-2017 were collected. Three sources of data from the Swedish National Board of Health and Welfare were extracted via the Cause of Death Register and the National Patient Register. RESULTS: Over 15 years, a total of 6609 cases occurred, resulting in an annual incidence of 4.66 per 100 000. The median age was 49 years (IQR 23-67) and 67% were males. Non-fatal drownings represented 51% (n = 3363), with an overall non-fatal to fatal ratio of 1:1, this being 8:1 for children (0-17 years of age). Non-fatal cases were more often female (36% vs. 30%; p < 0.001), younger 30 (IQR 10-56) vs. 60 (IQR: 45-72) (p < 0.001) and of unintentional nature (81% vs. 55%; p < 0.001). The overall incidence decreased over time from 5.6 to 4.1 per 100 000 (p < 0.001). The highest rate of 30-day survival was found in females 0-17 years (94%, 95% CI 91.1-95.5) and the lowest in males >66 years (28.7%, 95% CI 26.2-31.2). Although the incidence in children 0-4 years increased from 7.4 to 8.1 per 100 000 (p < 0.001), they demonstrated the highest non-fatal to fatal ratio (13:1). CONCLUSION: Drowning is declining but remains a consistent and underestimated public-health problem. Non-fatal drowning cases represent about half of the burden and characteristics differ from fatal drowning cases, being younger, more often female and of unintentional nature.

The use of drones and a machine-learning model for recognition of simulated drowning victims-A feasibility study.

BACKGROUND: Submersion time is a strong predictor for death in drowning, already 10 min after submersion, survival is poor. Traditional search efforts are time-consuming and demand a large number of rescuers and resources. We aim to investigate the feasibility and effectiveness of using drones combined with an online machine learning (ML) model for automated recognition of simulated drowning victims. METHODS: This feasibility study used photos taken by a drone hovering at 40 m altitude over an estimated 3000 m2 surf area with individuals simulating drowning. Photos from 2 ocean beaches in the south of Sweden were used to (a) train an online ML model (b) test the model for recognition of a drowning victim. RESULTS: The model was tested for recognition on n = 100 photos with one victim and n = 100 photos with no victims. In drone photos containing one victim (n = 100) the ML model sensitivity for drowning victim recognition was 91% (95%CI 84.9%-96.2%) with a median probability score that the finding was human of 66% (IQR 52-71). In photos with no victim (n = 100) the ML model specificity was 90% (95%CI: 83.9%-95.6%). False positives were present in 17.5% of all n = 200 photos but could all be ruled out manually as false objects. CONCLUSIONS: The use of a drone and a ML model was feasible and showed satisfying effectiveness in identifying a submerged static human simulating drowning in open water and favorable environmental conditions. The ML algorithm and methodology should be further optimized, again tested and validated in a real-life clinical study.

Coronary angiographic findings after cardiac arrest in relation to ECG and comorbidity.

INTRODUCTION: The relations between specific ECG patterns and coronary angiographic findings in cardiac arrest patients with different comorbidities are not properly assessed. More evidence is needed to identify patients with the highest risk for acute coronary artery disease as a cause of the cardiac arrest. This study aims to describe the coronary artery findings after cardiac arrest in relation to ECG and comorbidity. METHOD: A retrospective study of out-of-hospital cardiac arrest patients, with coronary angiography performed within 28 days. ECG on admission, comorbidity, PCI attempts and angiographic findings are described. Data were retrieved from national registries in Sweden. RESULTS: Among 1133 patients with available ECG and angiography information the mean age was 64 years. The rate of shockable rhythm was 79%. The total incidence of any significant stenosis in cardiac arrest patients without ST-elevation who underwent coronary angiography within 28 days was 71%. The incidence of any stenosis in patients with normal ECG was 62.1% and in patients with LBBB, 59.3%. In patients with ST-depression or RBBB, PCI attempts were made in 47.1% and 42.4% respectively, compared with 33.3% in patients with normal ECG. Among patients without ST-elevation, those with diabetes mellitus and those with initial shockable rhythm respectively, 84.8% and 71.5 had at least one significant stenosis. CONCLUSION: Our study suggests, that evaluation of ECG patterns and comorbidities in out-of-hospital cardiac arrest patients without ST-segment elevation may be important to identify those with a high risk of coronary artery lesions that could benefit from early revascularization.

Drone delivery of an automated external defibrillator - a mixed method simulation study of bystander experience.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) affects some 275,000 individuals in Europe each year. Time from collapse to defibrillation is essential for survival. As emergency medical services (EMS) response times in Sweden have increased, novel methods are needed to facilitate early treatment. Unmanned aerial vehicles (i.e. drones) have potential to deliver automated external defibrillators (AED). The aim of this simulation study was to explore bystanders' experience of a simulated OHCA-situation where a drone delivers an AED and how the situation is affected by having one or two bystanders onsite. METHODS: This explorative simulation study used a mixed methodology describing bystanders' experiences of retrieving an AED delivered by a drone in simulated OHCA situations. Totally eight participants were divided in two groups of bystanders a) alone or b) in pairs and performed CPR on a manikin for 5 minutes after which an AED was delivered by a drone at 50 m from the location. Qualitative data from observations, interviews of participants and video recordings were analysed using content analysis alongside descriptive data on time delays during bystander interaction. RESULTS: Three categories of bystander experiences emerged: 1) technique and preparedness, 2) support through conversation with the dispatcher, and 3) aid and decision-making. The main finding was that retrieval of an AED as delivered by a drone was experienced as safe and feasible for bystanders. None of the participants hesitated to retrieve the AED; instead they experienced it positive, helpful and felt relief upon AED-drone arrival and were able to retrieve and attach the AED to a manikin. Interacting with the AED-drone was perceived as less difficult than performing CPR or handling their own mobile phone during T-CPR. Single bystander simulation introduced a significant hands-off interval when retrieving the AED, a period lasting 94 s (range 75 s-110 s) with one participant compared to 0 s with two participants. CONCLUSION: The study shows that it made good sense for bystanders to interact with a drone in this simulated suspected OHCA. Bystanders experienced delivery of AED as safe and feasible. This has potential implications, and further studies on bystanders' experiences in real cases of OHCA in which a drone delivers an AED are therefore necessary.

Potential organ donors after Out-of-Hospital Cardiac Arrest during a ten-year period in Stockholm, Sweden.

BACKGROUND: Donation after brain death (DBD) is current praxis in Sweden. Circulatory death is far more common. Donation from patients suffering Out-of-Hospital Cardiac Arrest (OHCA) may have the potential to increase the organ-donor pool. The aim of this study was to describe the potential donor pool and its characteristics if uncontrolled donation after circulatory death (uDCD) were to be implemented in the metropolitan area of Stockholm, Sweden. METHODS: A retrospective analysis was made using data from the Swedish Register for cardiopulmonary resuscitation (SRCR) between 2006 and 2015. Evaluation of potential organ donors was made using selection criteria from five previously published protocols concerning uDCD. RESULTS: When applying different criteria from each of the five studied protocols in a total of 9,793 cases of OHCA, between 7.5% (n=732) and 1.5% (n=150) of the patients were found to be potential candidates for uDCD. The median age of the sampled uDCD candidates in each protocol was between 48 and 57 years. Male donors were found in 67-76% of all cases. CONCLUSION: Although not taking important real-life limitations into account, our results indicate that implementation of a uDCD programme may substantially increase the number of potential organ donors in Stockholm.

Experiences and outcome from the implementation of a national Swedish automated external defibrillator registry.

BACKGROUND: Early cardiopulmonary resuscitation (CPR) and defibrillation with an Automated External Defibrillator (AED) increase survival from out-of-hospital cardiac arrest (OHCA). Although international guidelines recommend the use of AED registries to increase AED use, little is known about implementation. The aim of this paper is to describe the development of a national AED registry, to analyse the coverage and barriers to register AEDs. METHODS: The Swedish AED Registry (SAEDREG) was initiated in 2009 with the purpose of gathering the data of all public AEDs in Sweden. Data on all AEDs between 2013 and 2016 were included in the study. Additionally, data of non-registered AEDs was collected in one region using a survey to AED owners focusing on AED functionality. RESULTS: The number of AEDs doubled between 2013-2016. A total of 6703 AEDs (30%) were removed due to unavailability of validation. At the end of 2016, AEDs were most frequently registered in offices and workplaces, 45% (n = 7241) followed by shops, 7% (n = 1200). In the Gotland region, 218 AEDs, 57% (n = 124) were registered in the SAEDREG. Of n = 94 Non-registered AED functionality was high, the main reason not to register was unawareness of the SAEDREG, 74.5%. Of those aware of the register but not having registered, 25% stated "hard to register" as cause. CONCLUSIONS: A national AED registry may gather information of AEDs on a national level. Although numbers have doubled between 2013-2016 in Sweden, a large proportion is still non-registered. More awareness of the registry and easier registration process is needed. General AED functionality seems high regardless of registered or non-registered AEDs. A key area for future research may be to use AED-registers to ascertain effectiveness of AED programs in terms of actual patient outcome.

Intensive care admissions due to poisoning.

BACKGROUND: Poisoning represents a significant part of admissions to intensive care units. The aim of this nationwide study was to describe recent national quality register data of demographics and mortality for these patients. METHOD: A retrospective national observational study including all patients over 19 years admitted to an ICU in Sweden, between 1 January 2010 and 31 December 2011, with an ICD-10 code for poisoning. The data were collected from three national registers (The Swedish Intensive Care Register, The National Patient Register, and The Cause of Death Register). RESULTS: The incidence of ICU-treated poisonings was 43/100,000. Twenty-one per cent (n = 8155) of all poisoned patients seeking medical care were admitted to the ICU. Their median age was 38 years (q1-q3: 26-51), as many men as women and 46.5% (n = 3790) had a previous registered poisoning. A mix of different substances was the most common type of suspected poisoning (29.7%, n = 2424). The in-hospital mortality was 1.9% and was correlated to invasive mechanical ventilation (OR 6.91 CI 95% 4.59-10.42), age > 40 (OR 4.54 CI 95% 2.86-7.21) and no previous hospitalisation for poisoning (OR 3.23 CI 95% 2.06-5.07). For 78.3% (n = 119) of the deceased patients, the fatal poisoning was their first diagnosed poisoning. The 30-day mortality was 2.7%, a majority died from poisoning (P < 0.01). CONCLUSION: In Sweden, patients treated in the ICU due to poisoning represent a fifth of all poisoned patients seeking medical care. Older men with no previous poisoning were considered a high-risk group.

Drones may be used to save lives in out of hospital cardiac arrest due to drowning.

BACKGROUND: Drowning leading to out-of-hospital cardiac arrest (OHCA) and death is a major public health concern. Submersion with duration of less than 10min is associated with favorable neurological outcome and nearby bystanders play a considerable role in rescue and resuscitation. Drones can provide a visual overview of an accident scene, their potential as lifesaving tools in drowning has not been evaluated. AIM: The aim of this simulation study was to evaluate the efficiency of a drone for providing earlier location of a submerged possible drowning victim in comparison with standard procedure. METHOD: This randomized simulation study used a submerged manikin placed in a shallow (<2m) 100×100-m area at Tylösand beach, Sweden. A search party of 14 surf-lifeguards (control) was compared to a drone transmitting video to a tablet (intervention). Time from start to contact with the manikin was the primary endpoint. RESULTS: Twenty searches were performed in total, 10 for each group. The median time from start to contact with the manikin was 4:34min (IQR 2:56-7:48) for the search party (control) and 0:47min (IQR 0:38-0:58) for the drone-system (intervention) respectively (p<0.001). The median time saved by using the drone was 3:38min (IQR 2:02-6:38). CONCLUSION: A drone transmitting live video to a tablet is feasible, time saving in comparison to traditional search parties and may be used for providing earlier location of submerged victims at a beach. Drone search can possibly contribute to earlier onset of CPR in drowning victims.

Medical versus non medical etiology in out-of-hospital cardiac arrest-Changes in outcome in relation to the revised Utstein template.

INTRODUCTION: The Utstein-style recommendations for reporting etiology and outcome in out-of-hospital cardiac arrest (OHCA) from 2004 have recently been revised. Among other etiologies a medical category is now introduced, replacing the cardiac category from Utstein template 2004. AIM: The aim of this study is to describe characteristics and temporal trends from reporting OHCA etiology according to the revised Utstein template 2014 in regards to patient characteristics and 30-day survival rates. METHODS: This registry study is based on consecutive OHCA cases reported from the Emergency medical services (EMS) to the Swedish Registry of Cardiopulmonary Resuscitation (SRCR) 1992-2014. Characteristics, including a presumed cardiac etiology in Utstein template 2004, were transcribed to a medical etiology in Utstein template 2014. RESULTS: Of a total of n=70,846 cases, 92% were categorized as having a medical etiology and 8% as having a non-medical cause. Using the new classifications, the 30-day survival rate has significantly increased over a 20-year period from 4.7% to 11.0% in the medical group and from 3% to 9.9% in the non-medical group (p≤0.001). Trauma was the most common cause in OHCA of a non-medical etiology (26%) with a 30-day survival rate of 3.4% whilst drowning and drug overdose had the highest survival rates (14% and 10% respectively). CONCLUSION: Based on Utstein 2014 categories of etiology, overall survival after OHCA with a medical etiology has more than doubled in a 20-year period and tripled for non-medical cases. Patients with a medical etiology found in a shockable rhythm have the highest chance of survival. There is great variability in characteristics among non-medical cases.

Unmanned aerial vehicles (drones) in out-of-hospital-cardiac-arrest.

BACKGROUND: The use of an automated external defibrillator (AED) prior to EMS arrival can increase 30-day survival in out-of-hospital cardiac arrest (OHCA) significantly. Drones or unmanned aerial vehicles (UAV) can fly with high velocity and potentially transport devices such as AEDs to the site of OHCAs. The aim of this explorative study was to investigate the feasibility of a drone system in decreasing response time and delivering an AED. METHODS: Data of Global Positioning System (GPS) coordinates from historical OHCA in Stockholm County was used in a model using a Geographic Information System (GIS) to find suitable placements and visualize response times for the use of an AED equipped drone. Two different geographical models, urban and rural, were calculated using a multi-criteria evaluation (MCE) model. Test-flights with an AED were performed on these locations in rural areas. RESULTS: In total, based on 3,165 retrospective OHCAs in Stockholm County between 2006-2013, twenty locations were identified for the potential placement of a drone. In a GIS-simulated model of urban OHCA, the drone arrived before EMS in 32 % of cases, and the mean amount of time saved was 1.5 min. In rural OHCA the drone arrived before EMS in 93 % of cases with a mean amount of time saved of 19 min. In these rural locations during (n = 13) test flights, latch-release of the AED from low altitude (3-4 m) or landing the drone on flat ground were the safest ways to deliver an AED to the bystander and were superior to parachute release. DISCUSSION: The difference in response time for EMS between urban and rural areas is substantial, as is the possible amount of time saved using this UAV-system. However, yet another technical device needs to fit into the chain of survival. We know nothing of how productive or even counterproductive this system might be in clinical reality. CONCLUSIONS: To use drones in rural areas to deliver an AED in OHCA may be safe and feasible. Suitable placement of drone systems can be designed by using GIS models. The use of an AED equipped drone may have the potential to reduce time to defibrillation in OHCA.

Aspects on the increase in bystander CPR in Sweden and its association with outcome.

AIM: To describe changes in the proportion of bystanders performing cardiopulmonary resuscitation (CPR) in out of hospital cardiac arrest (OHCA) in Sweden and to study the impact of bystander CPR on ventricular fibrillation and on survival during various times. PATIENTS AND METHODS: All patients who suffered from OHCA in Sweden in whom CPR was attempted and who were included in the Swedish cardiac arrest register (SCAR) between 1992 and 2005. Crew witnessed cases were excluded. RESULTS: In all 34,125 patients were included in the survey. Among witnessed OHCA the proportion of patients receiving bystander CPR increased from 40% in 1992 to 55% in 2005 (p<0.0001). In non-witnessed OHCA the corresponding proportion increased from 22% to 44% (p<0.0001). There was a significant increase in bystander CPR regardless of age, sex and place. The increase was only found when CPR was performed by lay persons (21% in 1992 to 40% in 2005; p<0.0001). Bystander CPR was associated with an increased proportion of patients found in a shockable rhythm and a lower number of shocks to receive return of spontaneous circulation. Bystander CPR was associated with a similar increase in survival early and late in the evaluation. CONCLUSION: There was a marked increase in bystander CPR in OHCA, when performed by lay persons, during the last 14 years in Sweden. Bystander CPR was associated with positive effects both on ventricular fibrillation and survival.

The role of profilin in actin polymerization and nucleotide exchange.

Properties of human profilin I mutated in the major actin-binding site were studied and compared with wild-type profilin using beta/gamma-actin as interaction partner. The mutants ranged in affinity, from those that only weakly affected polymerization of actin to one that bound actin more strongly than wild-type profilin. With profilins, whose sequestering activity was low, the concentration of free actin monomers observed at steady-state of polymerization [Afree], was close to that seen with actin alone ([Acc], critical concentration of polymerization). Profilin mutants binding actin with an intermediate affinity like wild-type profilin caused a lowering of [Afree] as compared to [Acc], indicating that actin monomers and profilin:actin complexes participate in polymer formation. With a mutant profilin, which bound actin more strongly than the wild-type protein, an efficient sequestration of actin was observed, and in this case, the [Afree] at steady state was again close to [Acc], suggesting that the mutant profilin:actin had a greatly lowered ability to incorporate actin subunits at the (+)-end. The results from the kinetic and steady-state experiments presented are consonant with the idea that profilin:actin complexes are directly incorporated at the (+)-end of actively polymerizing actin filaments, while they do not support the view that profilin facilitates polymer formation.

Characterization of a mutant profilin with reduced actin-binding capacity: effects in vitro and in vivo.

We are investigating structure-function relationships in profilin and actin by site-specific mutagenesis using a yeast, Saccharomyces cerevisiae, expression system to produce wild-type and mutant proteins. This paper shows that deleting proline 96 and threonine 97, which are located close to the major actin binding site on profilin, did not significantly alter the interaction between profilin and phosphatidylinositol 4,5-bisphosphate, nor did it affect the profilin:poly(L-proline) interaction. The mutant protein, however, had a lower capacity to bind to actin in vitro than wild-type profilin, though it showed a slightly increased profilin-enhanced nucleotide exchange on the actin. When microinjected into Swiss 3T3 mouse fibroblasts or porcine aortic endothelial cells, the mutant profilin did not change the organization of the microfilament system like the wild-type profilin did. This provides further evidence that profilin controls microfilament organization in the cell by interacting directly with actin.

Isolation and characterization of two mutants of human profilin I that do not bind poly(L-proline).

A simple procedure for the isolation of profilin mutants having a reduced capacity to bind poly(L-proline) is used to isolate two mutants of human profilin I, W3N and H133S. Binding of the mutants to poly(L-proline), actin, and phosphatidylinositol (4,5)-bisphosphate (PIP2) was studied. Both mutations abolished the poly(L-proline)-binding activity of profilin. This suggests that the arrangement of the N- and C-terminal helices forming the poly(L-proline)-binding site depends on the stabilizing interaction between W3 and W31 in the underlying beta-strand, and that the H133S mutation in the C-terminal helix also must have distorted the arrangement of the terminal helices. Both mutations caused a reduced affinity for actin, with the W3N replacement having the most pronounced effect. This shows that structural changes in the poly(L-proline)-binding region of profilin can affect the distantly located actin-binding site. Thus, ligands influencing the structure of the poly(L-proline)-binding site may regulate actin polymerization through profilin. This is consonant with the finding that PIP2, which changes the tryptophan fluorescence in wild-type profilin and dissociates the profilin:actin complex in vitro, binds more strongly to the W3N mutant profilin. Thus, the poly(L-proline)-binding surface represents a crucial regulatory site of profilin function.

Return to well-being and function after infrainguinal revascularization.

PURPOSE: The purpose of this study was to assess functional status, well-being, and symptom relief of patients after infrainguinal revascularization for severe peripheral vascular disease. METHODS: Two questionnaires were used to assess symptoms, functional status, and well-being before operation and 6 months after operation. Sociodemographics, comorbidities, indications for surgery, graft location, and morbidity, mortality, patency, and limb salvage rates were obtained via vascular registry. RESULTS: Of 318 patients who underwent revascularization over a 1-year period, 276 patients were asked to complete the questionnaires. Of the 156 patients who completed both questionnaires, mean age was 66 years, 67% were men, 84% had diabetes mellitus, and 83% had various heart-related conditions. Mean length of stay was 15.3 days. Distal graft sites were popliteal (29%), tibial/peroneal (40%), and pedal/plantar (31%). The operative morbidity rate was 21%, the cumulative primary graft patency rate was 93%, the cumulative secondary graft patency rate was 95%, and the limb salvage rate was 97% at 6 months. At follow-up, improved functioning of instrumental activities of daily living, mental well-being, and vitality were reported. Symptoms of calf cramping and toe or foot pain when walking and at rest were also improved. Sores or ulcers improved, but leg swelling did not. The only independent predictor of improved function and well-being was the patients' perception of their status at baseline: those patients who functioned better before operation reported improved function and well-being at 6 months. Only 45% of patients reported feeling "back to normal" at 6 months. CONCLUSION: Reported health status at baseline was a predictor of improved function, mental well-being, and resolution of symptoms after infrainguinal revascularization. Expected return to "normal" may take longer than 6 months.

Beyond all measures: criteria for the use and selection of a collection agency in a medical practice.

The need for protecting the accounts receivable of a medical practice by using collection agencies is well known. This paper provides background material and information necessary to establish criteria for placing accounts with a collection agency.

Leave no stone unturned.

The need for locating patients lost to follow-up is well known in epidemiologic research projects. This paper provides for the reader the basic tools, techniques, and methods that can be used to locate these patients.

Inhibition of gastric H+/K+-ATPase by substituted imidazo[1,2-a]pyridines.

A hydrophobic imidazopyridine, SCH 28080 (3-cyanomethyl-2-methyl-8-phenylmethoxy)imidazo[1,2-a]pyridine) has previously been shown to inhibit gastric acid secretion in vivo and in vitro. Studies of isolated gastric H+/K+-ATPase have demonstrated that SCH 28080 reversibly inhibited the enzyme and competitively interacted with the K+-stimulated ATPase and p-nitrophenylphosphatase activities of the H+/K+-ATPase. To elucidate the mechanism of inhibition further, for example to establish whether the inhibitor interaction occurs on the luminal or the cytosolic side of the enzyme or if compound pKa influences inhibition, SCH 28080 and three analogues have been studied. We have examined the effects on K+-stimulated ATPase activity in isolated ion-permeable membrane vesicles at different pH values and KCl concentrations. In ion-tight membrane fractions the effect on acid formation was estimated. The results are in agreement with the hypothesis that the protonated, and thus positively charged, form of SCH 28080 is the active species, and that the inhibitory effect is exerted by binding of the compound to the luminal side of the H+/K+-ATPase.