Clinical Data Extraction During Public Health Emergencies: A Blockchain Technology Assessment

Objective:We sought to explore the technical and legal readiness of healthcare institutions for novel data-sharing methods that allow clinical information to be extracted from electronic health records (EHRs) and submitted securely to the Food and Drug Administration''s (FDA''s) blockchain through a secure data broker (SDB).Materials and Methods:This assessment was divided into four sections: an institutional EHR readiness assessment, legal consultation, institutional review board application submission, and a test of healthcare data transmission over a blockchain infrastructure.Results:All participating institutions reported the ability to electronically extract data from EHRs for research. Formal legal agreements were deemed unnecessary to the project but would be needed in future tests of real patient data exchange. Data transmission to the FDA blockchain met the success criteria of data connection from within the four institutions'' firewalls, externally to the FDA blockchain via a SDB.Discussion:The readiness survey indicated advanced analytic capability in hospital institutions and highlighted inconsistency in Fast Healthcare Interoperability Resources format utilitzation across institutions, despite requirements of the 21st Century Cures Act. Further testing across more institutions and annual exercises leveraging the application of data exchange over a blockchain infrastructure are recommended actions for determining the feasibility of this approach during a public health emergency and broaden the understanding of technical requirements for multisite data extraction.Conclusion:The FDA''s RAPID (Real-Time Application for Portable Interactive Devices) program, in collaboration with Discovery, the Critical Care Research Network''s PREP (Program for Resilience and Emergency Preparedness), identified the technical and legal challenges and requirements for rapid data exchange to a government entity using the FDA blockchain infrastructure.

In the previous few decades, the world has been challenged by a barrage of public health emergencies (PHEs), from natural disasters to the infectious disease threats of SARS (severe acute respiratory syndrome), H1N1, Zika, Ebola, and the COVID-19 pandemic. We have learned that PHEs are imminent and that the need for preparedness is paramount to our nation''s resiliency.1In the wake of COVID-19, widespread data collection to understand the virus''s impact and effectiveness of treatment plans are needed. However, the United States'' ability to rapidly collect multisite patient data to understand the impact of a disease and develop a unified and effective response remains a considerable vulnerability despite significant health system and federal investment in electronic health records (EHRs).2,3 The all-hazardscore data set, created in 2015 to characterize serious illness,injuries, and resource requirements to devise a robustresponse to PHEs, remains a challenge to collect giventechnological and regulatory limitations3 in regard to datasharing. This has been observed in the response to COVID-19, where the lack of data to create consensus on effective treatment protocols has been hindered.4–6Several barriers exist to data sharing in PHEs, including academic competition and inadequate human and technological resources during responses to emergency.7–10 Neither a standard approach to data sharing nor a method to negotiate and enforce the requisite data legal agreements exists.11,12 Moreover, effective methods for addressing deficiencies or advancing data sharing in response to PHEs are lacking.12–14 A clear need exists to explore novel methods to secure data collection to bridge the gap in knowledge sharing during PHEs.The complexity of data sharing from disparate sources is a problem experienced in other industries. The finance sector requires the highest level of security to manage financial transactions with speed and integrity. Blockchain technology emerged in the finance industry as a disruptive technology aimed at facilitating a decentralized, secure, and distributed ledger of transactions on a global scale.15,16 Blockchain technology works as blocks of information across a computer network; when chained together, these blocks create a single data asset.Blockchain has been suggested as an information infrastructure that can be used to advance knowledge sharing in the public sector.17 The decentralized nature of blockchain allows for interoperability,15 which is a key functionality needed to enable data sharing among hospital systems. The use of blockchain in medicine has the potential to revolutionize healthcare''s approach to data access, storage, and security17–19 by providing a method to share confidential patient information across many sites regardless of the local technical infrastructure. Large-scale data sharing would contribute to more robust medical research, advanced analytics (e.g., artificial intelligence), and the ability to benchmark the quality of care across institutions.The Food and Drug Administration (FDA) partnered with the Society of Critical Care Medicine''s Discovery, the Critical Care Research Network''s Program for Resilience and Emergency Preparedness (PREP; referred to as “Discovery PREP” hereafter) to explore the feasibility of using blockchain for multisite healthcare data collection in preparation for the required rapid data sharing during a PHE. Discovery PREP is one of many networks forming the Resilience Intelligence Network (RIN) with a combined focus on the nation''s resilience, preparedness, and response.2Discovery PREP and the FDA Real-Time Application for Portable Devices (RAPID) program20 collaborated to test the use of RAPID''s blockchain technology to determine the technical, legal, and resource challenges in the healthcare context. The RAPID program was designed to facilitate the automated extraction of key information from EHR systems needed to respond to adverse events without adding to the burden of data collection on healthcare practitioners.     

Nurse and Pharmacist Knowledge of Intravenous Smart Pump System Setup Requirements

Objective:The primary purpose of this research was to describe nurse and pharmacist knowledge of setup requirements for intravenous (IV) smart pumps that require head height differentials for accurate fluid flow.Methods:A secondary analysis of anonymous electronic survey data using a database of prerecruited clinicians was conducted. A survey was sent by email to 173 pharmacists and 960 nurses. The response rate for pharmacists was 58% (100 of 173), and the response rate for nurses was 52% (500 of 960). After removing respondents who did not provide direct care and who did not use a head height differential IV infusion system, the final sample for analysis was 186 nurses and 25 pharmacists.Results:Overall, less than one-half of respondents (40%) were aware that manufacturer guidelines for positioning the primary infusion bag relative to the infusion pump were available. Slightly more (49.5%) were aware of the required head height differentials for secondary infusion. Only five respondents selected the correct primary head height, eight respondents selected the correct secondary head height, and one respondent selected both the correct primary and secondary head heights.Conclusion:The results of this study identify a substantial lack of knowledge among frontline clinicians regarding manufacturer recommendations for accurate IV administration of primary and secondary infusions for head height differential infusion systems. Both increased clinician education and innovative technology solutions are needed to improve IV smart pump safety and usability.

Large-volume intravenous (IV) smart pumps are the most widely used infusion devices in U.S. acute care hospitals due to their versatility in administering both fluids and medications.1,2 Recent data from U.S. acute care settings support an adoption rate of 99% for IV smart pumps with built-in dose error reduction software designed to mitigate medication administration errors.3 Although data support that IV smart pumps can reduce medication administration errors, they have not eliminated error, including serious adverse drug events with high-alert medications.4–10Secondary medication administration by large-volume IV smart pump is used extensively in U.S. acute care settings for administering IV medications ordered for one-time or intermittent dosing. The most commonly used method for secondary administration requires the primary continuous infusion to pause during the secondary infusion, then resume automatically after the secondary infusion is complete.1,11–13 The secondary infusion delivery method typically is used for administration of antibiotics and electrolyte replacement therapy.14Research has identified secondary medication infusions as particularly error prone.12,14 Both the setup and usability of most IV smart pump systems are complex, vary among different IV smart pump types, and have numerous associated failure modes that are not easily detected at the point of care.12 The majority of secondary medications are infused using the “head height differential” method, which requires a differential between the top of the fluid level in the primary and secondary fluid containers. These differentials generate the hydrostatic pressure required to close the primary tubing back-check valve and facilitate accurate secondary medication infusion (Figure 1).Open in a separate windowFigure 1.Required components for secondary medication infusion using the head height differential method. Used with permission from Karen K. Giuliano.IV smart pump systems from BD/Alaris, Baxter/Sigma, B. Braun, and Zyno use this method, with each having specific head height differentials and setup requirements.15–18 In contrast, a cassette pumping mechanism is used for other devices (e.g., manufactured by ICU Medical Plum and Ivenix) pumps. The user setup requirements for these cassette systems do not require a head height differential or back-check valve. Instead, when administering a secondary medication, the cassette provides a separate fluid path for secondary infusion, which is controlled independently from the primary infusion.It is important for nurses to be educated regarding the setup requirements of the IV smart pump system they are using, in order to avoid potentially dangerous secondary medication error caused by inaccurate flow.     

Thermal Disinfection Validation: The Relationship Between A0 and Microbial Reduction

Validating a thermal disinfection process for the processing of medical devices using moist heat via direct temperature monitoring is a conservative approach and has been established as the A₀ method. Traditional use of disinfection challenge microorganisms and testing techniques, although widely used and applicable for chemical disinfection studies, do not provide as robust a challenge for testing the efficacy of a thermal disinfection process. Considerable research has been established in the literature to demonstrate the relationship between the thermal resistance of microorganisms to inactivation and the A₀ method formula. The A₀ method, therefore, should be used as the preferred method for validating a thermal disinfection process using moist heat.

Disinfection, which is defined as reducing the number of viable microorganisms on a product to a level previously specified as appropriate for its intended further handling or use, can be achieved thermally by the action of moist heat.1 Thermal disinfection during the processing of medical devices, typically performed in a washer-disinfector, is widely used for two purposes. The first is for reducing product bioburden (disinfection) either as a terminal step (e.g., for noncritical or semicritical devices) or prior to packaging and sterilization (e.g., for critical devices) in preparation for patient use. The second is to render the devices safe for handling for central service professionals during inspection and packaging.2,3 Thermal disinfection requirements therefore should consider the potential levels of microbial contamination on reusable devices after use, the desired level of reduction to render those devices safe for handling and for their intended purpose, and the reliability of the disinfection process to consistently achieve that endpoint.The microbial load on device types after patient use has been established in the literature and can vary depending on the typical clinical use of the device. For example, critical (surgical) devices, on average, have demonstrated relatively low levels of viable microorganisms (bioburden level <10² colony-forming units [CFU]/cm²).4 However, these same studies have shown the concentration of other testing analytes (e.g., protein, total organic carbon, hemoglobin) to be more noteworthy. Although the data indicate that residual clinical soil (e.g., human secretions, blood, tissue) can harbor microorganisms, the incoming product bioburden levels are far below the microbial populations challenged during an overkill sterilization process (e.g., moist heat or gaseous processes).Conservative sterilization processes have been demonstrated to achieve at least a 12-log₁₀ reduction of microorganisms with a known higher resistance versus typical bioburden.3,5 Cleaning, which is defined as the removal of contamination from an item to the extent necessary for its further processing and its intended subsequent use, is an important step to render the device ready for sterilization and will further reduce the levels of microorganisms prior to sterilization. Therefore, with critical devices, adequate cleaning followed by sterilization is the minimum requirement to ensure the device is safe for patient use.It is not likely that, for the intended use of the device, a disinfection process is strictly necessary as an intermediate step prior to sterilization. A benefit may exist to having an interim disinfection step to render the device safe for handling during inspection and packaging for sterilization. For example, the expectation in the Occupational Safety and Health Administration''s Bloodborne Pathogens standard 29 CFR 1910.1030 is that an employer will minimize the occupational exposure to bloodborne pathogens.Thermal disinfection has been used by sterile processing departments as a universal precaution to reduce the risk of exposure to processing personnel postcleaning. Although routine thermal disinfection at less than 100°C (212°F) may not be effective in deactivating all types of microorganisms (e.g., certain types of bacteria spores), it is a reliable and consistent disinfection process. As the temperature increases above a certain point (typically ≥70°C or 158°F), so does the activity against microorganisms, with variable intrinsic and acquired resistance mechanisms to heat.3 Thermal disinfection therefore will provide processing personnel with a minimized risk of bloodborne pathogens exposure.In other situations, the microbiological load can be much higher (e.g., with flexible endoscopes used in the gastrointestinal system6) or more variable (e.g., with noncritical devices or surfaces depending on their use7). Where practical, thermal disinfection is still viewed as the preferred and more reliable method to render these devices safe for use due to its known efficacy against microbial pathogens.5 Chemical disinfection generally is only considered if thermal disinfection cannot be applied (e.g., due to thermo-sensitivity of device or surface materials).     

Even the Simplest Devices May Malfunction: Split Septum Design Revisited

Split septum medical devices are used in tubing for intravenous (IV) fluid administration—an extremely common clinical task. These tubing caps contain a needleless, valveless system that allows fluid to flow directly through the lumen of the catheter but prevents backflow of fluid or blood when the tubing extension is not connected. We experienced complete failure of a needle-free connector extension set with a Luer-access split septum device in multiple patients due to the split septum remaining fused and essentially unsplit despite being connected on both ends. This led to an adverse event in a patient due to repeated unnecessary IV insertion attempts. This case shows how even the simplest of devices can malfunction and highlights the need for vigilance in clinical practice.

Split septum medical devices are used in tubing for intravenous (IV) fluid administration—an extremely common clinical task. Typically, the angiocatheter is inserted into a vein and connected to a short tubing extension that is capped by split septum ends. The split septum cap then can be conveniently connected to the longer IV tubing, which is connected to the infusion and exchanged as needed.These tubing caps contain a needleless, valveless system that allows fluid to flow directly through the lumen of the catheter while also preventing backflow of fluid or blood when the tubing extension is not connected. This is achieved through a simple design of a prepierced rubber diaphragm. When the blunt cannula of the tubing is connected, it pierces the diaphragm open, allowing fluid to flow. Conversely, when the tubing is disconnected, the diaphragm acts as a physical barrier to flow and to the entry of bacteria.In contrast, mechanical valve devices consist of centerpieces that open on the external connection surface. When the Luer end pushes the centerpiece downward, internal components move to allow the flow of fluid within the device. This is commonly achieved through an elastic spring-like mechanism that keeps the centerpiece in the closed position when disconnected. Split septum designs, on the other hand, lack these internal moving parts.1 Because of their 64% to 70% lower catheter-related blood stream infection (CRBSI) rates, in 2011, the Centers for Disease Control and Prevention released a Category II recommendation favoring split septum valve devices over mechanical valve devices.2–5 These needleless designs have gained favor in clinical practice since they reduce needle stick injuries and decrease the rate of CRBSI.6Over the years, several engineering features have been favored when designing needle-free connectors (NFCs). These include a direct fluid pathway with minimal tortuosity, Luer access with minimal or no blood reflux, closed-system feature, and lack of a clamping sequence.7 Implementing these features minimizes biofilm development in the internal luminal surface of the device and decreases the risk of red blood cell hemolysis, in turn minimizing the risk of CRBSI, fibrin clot formation, and occlusion.7,8Typically, clinical practices purchase a single type of NFC model for routine use. Usually, the NFC is already attached to the short tubing extension. A given healthcare facility is likely to stock one pediatric model and a separate adult model. In our opinion, the parameter with the greatest influence on the average clinician''s decision regarding whether to use the NFC is the gauge diameter of the connector in the context of the clinical need for the IV. For example, if a large-bore IV is inserted for the purpose of massive resuscitation, and the available NFC was of a smaller gauge than the IV and tubing, then the clinician will likely discard it from the connector.A common NFC is the BD Q-Syte (BD, Franklin Lakes, NJ). Its intraluminal fluid pathway is not laminar and promotes turbulent fluid dynamic.7 It follows a negative displacement of fluid,7 meaning that once the NFC is connected to the tubing on both ends, fluid moves toward the patient and, when it is disconnected, blood refluxes into the catheter.Hull et al.8 studied the differences in blood reflux experienced among negative, positive, and neutral displacement NFC designs. They found a reflux volume of 9.73 to 50.34 μL for negative displacement, 3.60 to 10.80 μL for neutral displacement, and 0.02 to 1.73 μL for pressure-activated antireflux NFC. Although less reflux volume was noted on the pressure-activated antireflux NFCs, the authors concluded the importance of choosing a NFC based on performance of individual connector design rather than the displacement of fluid.8The current prevention guidelines continue to recommend the use of neutral-valve NFCs, as they have demonstrated prevention in occlusions and infections.9–12 Despite the impressive engineering considerations, our clinical experience highlights the susceptibility of malfunction in designs.Over the course of a year, we experienced complete failure of the BD Q-Syte 15-cm extension set with a Luer-access split septum device in five patients because the split septum remained fused and essentially unsplit despite being connected on both ends. This led to an adverse event in one of the patients. The Luer tip was inserted to the Luer-access split septum device and all clamps were unlocked; however, flushing of the line failed. IV access was attempted multiple times before it was noticed that blood was returning from the angiocatheter. Troubleshooting revealed that the NFC was impervious.When the Luer tip was disconnected from the split septum, patency of the tubing was confirmed. In a patient with more limited IV access, this could have resulted in greater harm by potentially wasting the valuable peripheral access sites and ultimately necessitating a central-line insertion procedure and escalating the risk.Of note, this medical device was subject to a Class 1 recall by the Food and Drug Administration in 2010 due to a manufacturing defect of the opposite etiology, whereby the septum would not seal and therefore could allow air entry resulting in an air embolism.13 The problem we have encountered is that, occasionally, the split septum does not split. Thankfully, our patient only suffered pain from numerous sticks.We continue to use this NFC in our clinical practice. Since the incident described here, we confirm proper functioning of the device by observing IV fluid flow out of the Luer tip and visually confirm patency of the system before connecting the tubing extension to the angiocatheter.Occasionally, we encounter repetition of such problems with the device septum. If the clinicians themselves did not prepare the flushed tubing, it may be advisable for them to test the tubing by opening the valve prior to connecting. Based on our anecdotal experience, we estimate the incidence of this product malfunction to be about five per 1,000 cases.In our opinion, in some clinical situations, it is certainly reasonable to refrain from using a connector extension and thereby avoid the need for a split septum device, or another NFC altogether, by connecting the IV tubing directly to the angiocatheter. For example, in a minor outpatient same-day procedure (e.g., a cataract surgery with light sedation, minimal anticipated blood loss, no expected need for IV tubing exchange, and a plan for the whole tubing and angiocatheter to be removed shortly after the procedure), skipping the use of the connector seems reasonable. This case highlights how even the simplest of devices can malfunction and, most importantly, the need for vigilance in clinical practice.     

Determining EMC Test Levels for Implantable Devices in Bipolar Lead Configuration

Certain low-frequency magnetic fields cause interference in implantable medical devices. Electromagnetic compatibility (EMC) standards prescribe injecting voltages into a device under evaluation to simplify testing while approximating or simulating real-world exposure situations to low-frequency magnetic fields. The EMC standard ISO 14117:2012, which covers implantable pacemakers and implantable cardioverter defibrillators (ICDs), specifies test levels for the bipolar configuration of sensing leads as being one-tenth of the levels for the unipolar configuration. The committee authoring this standard questioned this testing level difference and its clinical relevance. To evaluate this issue of EMC test levels, we performed both analytical calculations and computational modeling to determine a basis for this difference. Analytical calculations based upon Faraday''s law determined the magnetically induced voltage in a 37.6-cm lead. Induced voltages were studied in a bipolar lead configuration with various spacing between a distal tip electrode and a ring electrode. Voltages induced in this bipolar lead configuration were compared with voltages induced in a unipolar lead configuration. Computational modeling of various lead configurations was performed using electromagnetic field simulation software. The two leads that were insulated, except for the distal and proximal tips, were immersed in a saline-conducting media. The leads were parallel and closely spaced to each other along their length. Both analytical calculations and computational modeling support continued use of a one-tenth amplitude reduction for testing pacemakers and ICDs in bipolar mode. The most recent edition of ISO 14117 includes rationale from this study.

Implantable cardiac pacemakers are used in millions of patients to regulate or reproduce normal heart rhythm. Patients are candidates for a pacemaker when the heart''s natural rhythm is too slow or if a conduction block is present in the heart''s electrical system. An implantable cardioverter defibrillator (ICD) functions like a pacemaker, with the added function of being able to deliver a strong electrical shock to treat life-threatening arrhythmias. Both pacemakers and ICDs have lead(s) that extend from the metallic case under the skin, usually in the pectoral region, to the interior of the heart. Each lead has a distal tip electrode at the far end and one or more ring electrodes spaced a small distance closer to the metallic case (Figure 1). These electrodes are placed in one or more chambers of the heart. The implanted devices detect the heart''s intrinsic electrical activity via these electrodes to determine what stimulation to deliver. A voltage can be sensed between the tip electrode and the metallic case (unipolar) or between the tip and a ring electrode (bipolar). The choice of sensing is up to the clinician.Open in a separate windowFigure 1.Tip and ring electrodes are used for a bipolar configuration. For unipolar configuration, only the tip electrode is used.Pacemakers and ICDs are continuously sensing the heart''s electrical activity and are susceptible to electromagnetic interference (EMI), which may be interpreted as cardiac signals. EMI is a disturbance generated by an electrical source, such as a cell phone. EMI to pacemakers and ICDs is well known.1 Because pacemakers and ICDs sense frequencies between 1 and 500 Hz, they are most susceptible to low-frequency magnetic fields. The Food and Drug Administration recognizes ISO 14117:20192 as describing an electromagnetic compatibility (EMC) test method for pacemakers and ICDs.The Active Implants Joint Working Group 1 (ISO/TC 150 SC 6 JWG 1)3 is the standards group that authors the EMC standard ISO 14117. While writing the second edition of this standard, the group questioned the basis for the material published in the first edition. One topic of discussion was the requirement and lack of rationale in determining the appropriate test levels for bipolar lead configurations. The test levels described for a unipolar configuration are reasonably supported based partly on the reference levels in the European Commission Recommendation 5194 under certain assumptions of magnetic fields inducing a voltage in leads. However, the normative requirements of ISO 14117:2012 simply state, “Bipolar differential mode performance shall be tested using the test signal reduced to one-tenth amplitude” (referring to one-tenth of the test signal specified for devices with unipolar leads).5 The only rationale provided in ISO 14117:2012 is as follows: “Because of the close proximity of tip and ring electrodes, the applicable test signal is reduced to 10% of the common mode test signal amplitude.” No documented scientific basis exists for this 90% reduction for bipolar differential tests.The objectives of the current study were to determine the appropriate test levels below 10 MHz for the bipolar lead configuration and to provide a clear rationale for those levels. All implantable pacemakers and ICDs are tested to the ISO 14117 standard, and the large majority that are implanted are programmed to a bipolar lead configuration. The current study sought to improve understanding regarding whether implantable pacemakers and ICDs are tested to an adequate level.     

Medical Device Industry Approaches for Addressing Sources of Failing Cytotoxicity Scores

To ensure patient safety, medical device manufacturers are required by the Food and Drug Administration and other regulatory bodies to perform biocompatibility evaluations on their devices per standards, such as the AAMI-approved ISO 10993-1:2018 (ANSI/AAMI/ISO 10993-1:2018).However, some of these biological tests (e.g., systemic toxicity studies) have long lead times and are costly, which may hinder the release of new medical devices. In recent years, an alternative method using a risk-based approach for evaluating the toxicity (or biocompatibility) profile of chemicals and materials used in medical devices has become more mainstream. This approach is used as a complement to or substitute for traditional testing methods (e.g., systemic toxicity endpoints). Regardless of the approach, the one test still used routinely in initial screening is the cytotoxicity test, which is based on an in vitro cell culture system to evaluate potential biocompatibility effects of the final finished form of a medical device. However, it is known that this sensitive test is not always compatible with specific materials and can lead to failing cytotoxicity scores and an incorrect assumption of potential biological or toxicological adverse effects. This article discusses the common culprits of in vitro cytotoxicity failures, as well as describes the regulatory-approved methodology for cytotoxicity testing and the approach of using toxicological risk assessment to address clinical relevance of cytotoxicity failures for medical devices. Further, discrepancies among test results from in vitro tests, use of published half-maximal inhibitory concentration data, and the derivation of their relationship to tolerable exposure limits, reference doses, or no observed adverse effect levels are highlighted to demonstrate that although cytotoxicity tests in general are regarded as a useful sensitive screening assays, specific medical device materials are not compatible with these cellular/in vitro systems. For these cases, the results should be analyzed using more clinically relevant approaches (e.g., through chemical analysis or written risk assessment).

Medical devices are engineered to be of durable construction and to accommodate the functionality needed for proper device application. The biocompatibility of the materials, as well as their processing, is also important to ensure that the patients are not negatively affected by the devices when they enter the clinical setting. Certain materials of constructions used for medical devices (and manufacturing processes or processing aids) may contain chemicals that can lead to failing cytotoxicity scores using traditional, regulatory-mandated methodologies. Examples of common materials include plastics (e.g., polyethylene or polypropylene [co]polymers, polyvinyl chloride [PVC]) and metals (e.g., nitinol, copper [Cu]-containing alloys). Although providing stable and reliable materials for use in relation to performance parameters, various metals/alloys and plastics may evoke undesired cytotoxic effects. These effects might be observed as reduced cellular activity or decay in the in vitro assay, especially when standard methods and test parameters (e.g., extraction ratios) are used.1,2To prevent adverse effects (e.g., toxicity, or other types of biocompatibility-related issues) from occurring among patients and clinical end users, manufacturers are required to perform biocompatibility evaluations per guidance provided in e.g., ANSI/AAMI/ISO 10993-1:2018.3 This standard provides an overall framework for the biological evaluation, emphasizing a risk-based approach, as well as general guidance on relevant tests for specific types of contact to patients or users. Of note, traditional biocompatibility tests, within the battery of both in vivo and in vitro methods, could take up to 6 months (or take years, in the case of long-term systemic toxicity testing). Lengthy turnaround times stem from in vivo test methods, which are performed on animal models and include irritation, sensitization, systemic toxicity, genotoxicity, and carcinogenicity studies. Traditional in vitro tests involve exposure of cells or cellular material to device extracts in order to characterize toxicity in terms of cytotoxicity, genotoxicity, cellular metabolic activity, and aspects of hemocompatibility.3In recent years, as a complement to or a substitute for traditional testing methods, a risk-based approach using a chemical and materials characterization for evaluation of patient safety has become mainstream. The framework for this approach is provided in ISO 10993-18:2020.4 Moreover, the Association for the Advancement of Medical Instrumentation (AAMI) and, by extension, regulatory bodies (including the Food and Drug Administration [FDA] and International Organization for Standardization [ISO]) have driven the use of chemical and material characterization. Particularly for medical devices in long-term contact with patient (e.g., implantable devices), use of chemical and material characterization can reduce unnecessary animal testing and provide results that are scientifically sound and detailed, while being more cost and time efficient. For example, ISO 10993-13 highlights that a correctly conducted risk assessment can provide justification to exclude long-term biological testing, where the nature and extent of exposure confirms that the patient is being exposed to very low levels of chemicals that are below relevant toxicological thresholds.3Throughout the ISO 10993 series, it also is emphasized that conducting animal testing for biological risk evaluation should only be considered after all alternative courses of action (review of prior knowledge, chemical or physical characterization, in vitro evaluations, or alternative means of mitigation) have been exhausted. In addition, analytical chemistry used for chemical characterization can be used as a means for investigating possible culprits when traditional biocompatibility tests, such as cytotoxicity tests, fail, especially in cases where a known substance(s) in the material has cytotoxic potential (e.g., silver-infused wound dressing that provides antibacterial properties).However, it should be kept in mind that although chemistry can be a powerful tool in many cases, not all medical devices extracts are compatible with the analytical methods and instruments used, and these studies may not provide the full understanding of the toxicity profile of the device. In those cases, animal testing or further justification may still be needed to demonstrate a safe biocompatibility profile for the device.Cytotoxicity testing per AAMI/ISO 10993-5:2009/(R)20145 has historically been one of the most used (and is considered the most reactive) of the biocompatibility tests6,7 and can be efficiently used to detect abnormal effects to cells that may arise if harmful chemicals are present in device extracts. However, it also is recognized that cell-based test methods do not necessarily correlate to in vivo toxicological effects and actual clinical patient safety, often showing a reaction when no clinical adverse effects are known or expected to occur. For instance, some soluble metal ions (e.g., Cu, nickel [Ni]) are known to exert toxic effects on cells in an in vitro setting; however, their presence in surgical instruments and implants has demonstrated high patient tolerance and negligible effects upon clinical use.This article provides a brief evaluation of the clinical impact of metals and plasticizers commonly used in medical device materials that may lead to patient exposure during the use of devices, with emphasis given to those that may result in cytotoxicity failures in an in vitro setting. In addition, an approach to evaluating valid clinical risks using a toxicological risk assessment is discussed.     

Deviation from Clinical Routines Can Reveal Sources of Device Design Vulnerability

The ability to adequately ventilate a patient is critical and sometimes a challenge in the emergency, intensive care, and anesthesiology settings. Commonly, initial ventilation is achieved through the use of a face mask in conjunction with a bag that is manually squeezed by the clinician to generate positive pressure and flow of air or oxygen through the patient''s airway. Large or small erroneous openings in the breathing circuit can lead to leaks that compromise ventilation ability. Standard procedure in anesthesiology is to check the circuit apparatus and oxygen delivery system prior to every case. Because the face mask itself is not a piece of equipment that is associated with a source of leak, some common anesthesia machine designs are constructed such that the circuit is tested without the mask component. We present an example of a leak that resulted from complete failure of the face mask due to a tiny tear in its cuff by the patient''s sharp teeth edges. This subsequently prevented formation of a seal between the face mask and the patient''s face and rendered the device incapable of generating the positive pressure it is designed to deliver. This instance depicts the broader lesson that deviation from clinical routines can reveal unappreciated sources of vulnerability in device design.

Ventilation is the movement of air or gas from the external environment into the alveoli of the lungs. In the critical care setting, the ability to mechanically ventilate a patient in acute distress is a lifesaving skill, as these patients often cannot adequately breathe on their own. As such, ventilating is almost always more important than intubation per se. In emergencies, initial ventilation typically is established using a simple face mask in conjunction with a bag that the clinician manually squeezes to generate positive pressure and gas flow through the patient''s airway. These bags are commonly referred to as Ambu bags, a proprietary term that traces to a popular airway equipment brand. When a patient is breathing spontaneously, their inspiratory muscles, mainly the diaphragm, generate a pressure force that by convention is referred to as a “negative inspiratory force” or negative pressure that pulls outside air into the lungs. In contrast, when an inspiratory drive is absent, air or other gases can be “pushed” into the lungs by mechanical means (referred to clinically as positive pressure).Face masks are designed to have a soft-contoured, air-filled, cushion-like cuff that lies directly on the patient''s face, thereby allowing a seal to be formed over the mouth and nose (Figure 1). Achieving a proper seal is crucial to generating positive pressure. The cushion commonly consists of polyvinyl chloride plastisol due to its malleable properties.1 These masks are used extensively in anesthesiology because general anesthesia, and particularly intravenous (IV) anesthetics, often impede a patient''s ability to breathe on their own.Open in a separate windowFigure 1.Demonstration of a clinical face mask placement with the air-filled cuff cushion forming a seal around the face.Further, a paralytic medication is typically used in the setting of general anesthesia in order to optimize intubation conditions before an endotracheal tube is placed to secure the airway. The paralytic medication will completely prevent all skeletal muscle movements, including those of the diaphragm, hence eliminating any remaining spontaneous breathing drive that the patient may still have. The typical clinical sequence of events on induction (i.e., initiation of the anesthesia) of general anesthesia is to administer the IV anesthetic first and, only after adequate mask ventilation is confirmed, to then follow with a paralytic medication.In the event that mask ventilation fails (e.g., upper airway obstruction, equipment failure, or an unexpected airway pathology such as a tracheal fistula), the clinician may be able to backtrack to safety if a spontaneous respiratory drive is regained by the patient. Common IV induction agents such as propofol have the ideal pharmacokinetic property of a very short duration of action. Accordingly, their respiratory depressing effect can potentially be undone with the passage of time by opting to awaken the patient if ventilation cannot be achieved as expected2.Before each procedure, the standard of care in anesthesiology is to check the circuit apparatus as part of the anesthesia machine check.3 This machine check includes a positive pressure test whereby the breathing circuit is checked for leaks. The overall steps to the positive pressure test are outlined in Figure 2. Some anesthesia machines automatically perform the test on their own with the press of a button by the clinician. A common design in anesthesia machines includes a blank metal knob to which the circuit can be connected in order to close off the circuit and allow for pressurization by the machine (Figure 3). Such design requires intentional physical removal of the mask from the circuit in order to occlude the apparatus. The implicit assumption in this design is that the mask is reliable enough to be removed and excluded from the pressure test. This contrasts with the broad recognition that the mask is a vital component of the breathing circuit and without which the circuit is almost useless.Open in a separate windowFigure 2.Flowchart depicting the steps for performing a positive pressure test.Open in a separate windowFigure 3.Anesthesia machine circuit. Left: Face mask attachment connected. Right: Closed-off cap position for pressure test.We experienced failure of this type of mask and, at the time of the incident, were unable to identify its cause. After we induced general anesthesia, it was immediately evident that we could not generate positive pressure and failed to ventilate. After ruling out patient-specific causes that would interfere with ventilation, various external equipment-related reasons must be considered.The most common culprits for such a scenario are probably the presence of a leak somewhere along the path of oxygen flow or insufficient oxygen supply to the machine. These leaks can occur in the connections of the breathing circuit or within the anesthesia machine itself. At the time of our experience, we could not identify an apparent leak and the patient''s oxygen saturation rapidly desaturated as we were failing to ventilate adequately. Thankfully, intubation was successful, and ventilation was then established via the endotracheal tube.Afterwards, a close examination of the equipment eventually revealed a tear in the cuff of the mask. We believe that the mask was torn during induction when general anesthesia was initiated. This elderly patient had advanced dementia and refused to let the clinical team establish IV access. The decision was made to perform a mask induction in which inhaled anesthetic gases are used via the face mask instead of IV induction agents. This practice is common in young pediatric patients, for which IV access is challenging to achieve before induction of anesthesia. Given that our patient of this instance was elderly, he was missing numerous teeth and his remaining teeth were larger than those of a pediatric patient (Figure 4). When mask induction was initiated, the patient thrashed his head aggressively from side to side and grabbed the mask with his hands to forcefully remove it from his face. This necessitated the clinician to firmly hold the mask to the patient''s face. In this process, the sharp edges of the patient''s teeth likely caught the cuff and tore it.Open in a separate windowFigure 4.Actual patient''s dentition.Before this incident, we did not suspect the mask itself to be the equipment piece responsible for the leak. Given its exclusion from the pressure test, it is likely that the engineers who designed the anesthesia machine also did not think of it as a culprit for a leak. A leak around the mask is a common etiology of failed ventilation, but this occurs due to difficult airway features, such as a beard, deformed or abnormal facial structure, or conditions requiring considerably higher pressures to be generated (e.g., an obese patient).This patient''s airway was clinically unremarkable on exam during the preoperative physical evaluation. A leak around the mask was therefore not thought of and was low on the differential of problem etiology. Our general approach to diagnosing real-time leaks that occur after a proper machine check with a satisfactory pressure test was to focus on any changes that may have occurred after the test and to listen for audible signs of a leak. Before this incident, we partitioned leaks into two groups based on the physical size of the opening: large versus small equipment deformities. Our impression was that a large opening (e.g., a marked circuit disconnect) would be relatively obvious and visually apparent, whereas a small opening (e.g., tear, hole, loose connection fitting) would be more easily evident by an audible hissing sound. Our thought process was that a minor insult or opening in the circuit would still allow for some level of pressure to be generated within the apparatus and that this pressure escapes or leaks with turbulence and is therefore audible.As the above experience illustrates, the aforementioned dichotomy is a categorization not always maintained. The tear in the mask was tiny and on the inside portion of the mask (Figure 5), making it hard to visualize or hear. Nonetheless, because it was a tear in a cuff, it translated to a larger area of compromise that effectively prevented any positive pressure from being generated.Open in a separate windowFigure 5.Tear on the inside of the face mask cuff.This example demonstrates that even though the face mask itself does not take part in the positive pressure leak test, it can still be an important source of a major leak. Moreover, it highlights that when a medical device is used in a fashion at variance with its usual use or under altered conditions, extra vigilance to new sources of malfunction is warranted.     

Insights into the Problem of Alarm Fatigue with Physiologic Monitor Devices: A Comprehensive Observational Study of Consecutive Intensive Care Unit Patients

Purpose

Physiologic monitors are plagued with alarms that create a cacophony of sounds and visual alerts causing “alarm fatigue” which creates an unsafe patient environment because a life-threatening event may be missed in this milieu of sensory overload. Using a state-of-the-art technology acquisition infrastructure, all monitor data including 7 ECG leads, all pressure, SpO2, and respiration waveforms as well as user settings and alarms were stored on 461 adults treated in intensive care units. Using a well-defined alarm annotation protocol, nurse scientists with 95% inter-rater reliability annotated 12,671 arrhythmia alarms.

Results

A total of 2,558,760 unique alarms occurred in the 31-day study period: arrhythmia, 1,154,201; parameter, 612,927; technical, 791,632. There were 381,560 audible alarms for an audible alarm burden of 187/bed/day. 88.8% of the 12,671 annotated arrhythmia alarms were false positives. Conditions causing excessive alarms included inappropriate alarm settings, persistent atrial fibrillation, and non-actionable events such as PVC''s and brief spikes in ST segments. Low amplitude QRS complexes in some, but not all available ECG leads caused undercounting and false arrhythmia alarms. Wide QRS complexes due to bundle branch block or ventricular pacemaker rhythm caused false alarms. 93% of the 168 true ventricular tachycardia alarms were not sustained long enough to warrant treatment.

Discussion

The excessive number of physiologic monitor alarms is a complex interplay of inappropriate user settings, patient conditions, and algorithm deficiencies. Device solutions should focus on use of all available ECG leads to identify non-artifact leads and leads with adequate QRS amplitude. Devices should provide prompts to aide in more appropriate tailoring of alarm settings to individual patients. Atrial fibrillation alarms should be limited to new onset and termination of the arrhythmia and delays for ST-segment and other parameter alarms should be configurable. Because computer devices are more reliable than humans, an opportunity exists to improve physiologic monitoring and reduce alarm fatigue.     

Chapter 3: Small Molecules and Disease

“Big” molecules such as proteins and genes still continue to capture the imagination of most biologists, biochemists and bioinformaticians. “Small” molecules, on the other hand, are the molecules that most biologists, biochemists and bioinformaticians prefer to ignore. However, it is becoming increasingly apparent that small molecules such as amino acids, lipids and sugars play a far more important role in all aspects of disease etiology and disease treatment than we realized. This particular chapter focuses on an emerging field of bioinformatics called “chemical bioinformatics” – a discipline that has evolved to help address the blended chemical and molecular biological needs of toxicogenomics, pharmacogenomics, metabolomics and systems biology. In the following pages we will cover several topics related to chemical bioinformatics. First, a brief overview of some of the most important or useful chemical bioinformatic resources will be given. Second, a more detailed overview will be given on those particular resources that allow researchers to connect small molecules to diseases. This section will focus on describing a number of recently developed databases or knowledgebases that explicitly relate small molecules – either as the treatment, symptom or cause – to disease. Finally a short discussion will be provided on newly emerging software tools that exploit these databases as a means to discover new biomarkers or even new treatments for disease.

What to Learn in This Chapter

• The meaning of chemical bioinformatics
• Strengths and limitations of existing chemical bioinformatic databases
• Using databases to learn about the cause and treatment of diseases
• The Small Molecule Pathway Database (SMPDB)
• The Human Metabolome Database (HMDB)
• DrugBank
• The Toxin and Toxin-Target Database (T3DB)
• PolySearch and Metabolite Set Enrichment Analysis

This article is part of the “Translational Bioinformatics” collection for PLOS Computational Biology.

     

Validation of the Early Warning and Response System (EWARS) for dengue outbreaks: Evidence from the national vector control program in Mexico

BackgroundDuring 2017, twenty health districts (locations) implemented a dengue outbreak Early Warning and Response System (EWARS) in Mexico, which processes epidemiological, meteorological and entomological alarm indicators to predict dengue outbreaks and triggers early response activities.Out of the 20 priority districts where more than one fifth of all national disease transmission in Mexico occur, eleven districts were purposely selected and analyzed. Nine districts presented outbreak alarms by EWARS but without subsequent outbreaks (“non-outbreak districts”) and two presented alarms with subsequent dengue outbreaks (“outbreak districts”). This evaluation study assesses and compares the impact of alarm-informed response activities and the consequences of failing a timely and adequate response across the outbreak groups.MethodsFive indicators of dengue outbreak response (larval control, entomological studies with water container interventions, focal spraying and indoor residual spraying) were quantitatively analyzed across two groups (”outbreak districts” and “non-outbreak districts”). However, for quality control purposes, only qualitative concluding remarks were derived from the fifth response indicator (fogging).ResultsThe average coverage of vector control responses was significantly higher in non-outbreak districts and across all four indicators. In the “outbreak districts” the response activities started late and were of much lower intensity compared to “non-outbreak districts”. Vector control teams at districts-level demonstrated diverse levels of compliance with local guidelines for ‘initial’, ‘early’ and ‘late’ responses to outbreak alarms, which could potentially explain the different outcomes observed following the outbreak alarms.ConclusionFailing timely and adequate response of alarm signals generated by EWARS showed to negatively impact the disease outbreak control process. On the other hand, districts with adequate and timely response guided by alarm signals demonstrated successful records of outbreak prevention. This study presents important operational scenarios when failing or successding EWARS but warrants investigating the effectiveness and cost-effectiveness of EWARS using a more robust designs.     

Chapter 4: Protein Interactions and Disease

Proteins do not function in isolation; it is their interactions with one another and also with other molecules (e.g. DNA, RNA) that mediate metabolic and signaling pathways, cellular processes, and organismal systems. Due to their central role in biological function, protein interactions also control the mechanisms leading to healthy and diseased states in organisms. Diseases are often caused by mutations affecting the binding interface or leading to biochemically dysfunctional allosteric changes in proteins. Therefore, protein interaction networks can elucidate the molecular basis of disease, which in turn can inform methods for prevention, diagnosis, and treatment. In this chapter, we will describe the computational approaches to predict and map networks of protein interactions and briefly review the experimental methods to detect protein interactions. We will describe the application of protein interaction networks as a translational approach to the study of human disease and evaluate the challenges faced by these approaches.

What to Learn in This Chapter

• Experimental and computational methods to detect protein interactions
• Protein networks and disease
• Studying the genetic and molecular basis of disease
• Using protein interactions to understand disease

This article is part of the “Translational Bioinformatics” collection for PLOS Computational Biology.

     

FishSizer: Software solution for efficiently measuring larval fish size

1. Length and depth of fish larvae are part of the fundamental measurements in many marine ecology studies involving early fish life history. Until now, obtaining these measurements has required intensive manual labor and the risk of inter‐ and intra‐observer variability.
2. We developed an open‐source software solution to semi‐automate the measurement process and thereby reduce both time consumption and technical variability. Using contrast‐based edge detection, the software segments images of a fish larva into “larva” and “background.” Length and depth are extracted from the “larva” segmentation while taking curvature of the larva into consideration. The graphical user interface optimizes workflow and ease of usage, thereby reducing time consumption for both training and analysis. The software allows for visual verification of all measurements.
3. A comparison of measurement methods on a set of larva images showed that this software reduces measurement time by 66%–78% relative to commonly used software.
4. Using this software instead of the commonly used manual approach has the potential to save researchers from many hours of monotonous work. No adjustment was necessary for 89% of the images regarding length (70% for depth). Hence, the only workload on most images was the visual inspection. As the visual inspection and manual dimension extraction works in the same way as currently used software, we expect no loss in accuracy.

     

Chapter 7: Pharmacogenomics

There is great variation in drug-response phenotypes, and a “one size fits all” paradigm for drug delivery is flawed. Pharmacogenomics is the study of how human genetic information impacts drug response, and it aims to improve efficacy and reduced side effects. In this article, we provide an overview of pharmacogenetics, including pharmacokinetics (PK), pharmacodynamics (PD), gene and pathway interactions, and off-target effects. We describe methods for discovering genetic factors in drug response, including genome-wide association studies (GWAS), expression analysis, and other methods such as chemoinformatics and natural language processing (NLP). We cover the practical applications of pharmacogenomics both in the pharmaceutical industry and in a clinical setting. In drug discovery, pharmacogenomics can be used to aid lead identification, anticipate adverse events, and assist in drug repurposing efforts. Moreover, pharmacogenomic discoveries show promise as important elements of physician decision support. Finally, we consider the ethical, regulatory, and reimbursement challenges that remain for the clinical implementation of pharmacogenomics.

What to Learn in This Chapter

• Interactions between drugs (small molecules) and genes (proteins)
• Methods for pharmacogenomic discovery
  • Association- and expression-based methods
  • Cheminformatics and pathway-based methods
• Database resources for pharmacogenomic discovery and application (PharmGKB)
• Applications of pharmacogenomics into a clinical setting

This article is part of the “Translational Bioinformatics” collection for PLOS Computational Biology.

     

What really matters in end-of-life discussions? Perspectives of patients in hospital with serious illness and their families

Background:

The guideline-recommended elements to include in discussions about goals of care with patients with serious illness are mostly based on expert opinion. We sought to identify which elements are most important to patients and their families.

Methods:

We used a cross-sectional study design involving patients from 9 Canadian hospitals. We asked older adult patients with serious illness and their family members about the occurrence and importance of 11 guideline-recommended elements of goals-of-care discussions. In addition, we assessed concordance between prescribed goals of care and patient preferences, and we measured patient satisfaction with goals-of-care discussions using the Canadian Health Care Evaluation Project (CANHELP) questionnaire.

Results:

Our study participants included 233 patients (mean age 81.2 yr) and 205 family members (mean age 60.2 yr). Participants reported that clinical teams had addressed individual elements of goals-of-care discussions infrequently (range 1.4%–31.7%). Patients and family members identified the same 5 elements as being the most important to address: preferences for care in the event of life-threatening illness, values, prognosis, fears or concerns, and questions about goals of care. Addressing more elements was associated with both greater concordance between patients’ preferences and prescribed goals of care, and greater patient satisfaction.

Interpretation:

We identified elements of goals-of-care discussions that are most important to older adult patients in hospital with serious illness and their family members. We found that guideline-recommended elements of goals-of-care discussions are not often addressed by health care providers. Our results can inform interventions to improve the determination of goals of care in the hospital setting.In Canada, dying is often an in-hospital, technology-laden experience.^1–4 Rates of cardiopulmonary resuscitation (CPR) before death continue to increase among older adult patients in hospital,⁵ and one-fifth of deaths in hospital occur in an intensive care unit.^1,2,6,7 These observations contrast sharply with patient-reported preferences. A recent Canadian study found that 80% of older adult patients in hospital with a serious illness prefer a less aggressive and more comfort-oriented end-of-life care plan that does not include CPR.⁸Such patients and their families have identified communication with health care providers and decision-making about goals of care as high priorites for improving end-of-life care in Canada.^9,10 We define “decision-making about goals of care” as an end-of-life communication and decision-making process that occurs between a clinician and a patient (or a substitute decision-maker if the patient is incapable) in an institutional setting to establish a plan of care. Often, this process includes deciding whether to use life-sustaining treatments.¹¹ Current guidelines recommend that health care providers address 11 key elements when discussing goals of care with patients and families (Box 1).^12–14 However, these elements are mostly based on expert opinion and lack input from patients and their families.

Box 1:

Key elements of goals-of-care discussions with patients in hospital with serious illness^12–14

• Ask about previous discussions or written documentation about the use of life-sustaining treatments
• Offer a time to meet to discuss goals of care
• Provide information about advance care planning to review before conversations with the physician
• Disclose prognosis
• Ask about patients’ values (i.e., what is important to them when considering health care decisions)
• Provide information about outcomes, benefits and risks of life-sustaining treatments
• Provide information about outcomes, benefits and risks of comfort measures
• Prompt for additional questions about goals of care
• Provide an opportunity to express fears or concerns
• Ask about preferences for care in the event of a life-threatening illness
• Facilitate access to legal documents to record patients’ wishes

Our primary objective was to determine which of these elements are most important to patients and their families. In addition, we examined whether these discussions were associated with concordance between patients’ (or family members’) preferences and prescribed goals of care, and with satisfaction with end-of-life communication and decision-making.     

Beyond UHC: Monitoring Health and Social Protection Coverage in the Context of Tuberculosis Care and Prevention

Tuberculosis (TB) remains a major global public health problem. In all societies, the disease affects the poorest individuals the worst. A new post-2015 global TB strategy has been developed by WHO, which explicitly highlights the key role of universal health coverage (UHC) and social protection. One of the proposed targets is that “No TB affected families experience catastrophic costs due to TB.” High direct and indirect costs of care hamper access, increase the risk of poor TB treatment outcomes, exacerbate poverty, and contribute to sustaining TB transmission. UHC, conventionally defined as access to health care without risk of financial hardship due to out-of-pocket health care expenditures, is essential but not sufficient for effective and equitable TB care and prevention. Social protection interventions that prevent or mitigate other financial risks associated with TB, including income losses and non-medical expenditures such as on transport and food, are also important. We propose a framework for monitoring both health and social protection coverage, and their impact on TB epidemiology. We describe key indicators and review methodological considerations. We show that while monitoring of general health care access will be important to track the health system environment within which TB services are delivered, specific indicators on TB access, quality, and financial risk protection can also serve as equity-sensitive tracers for progress towards and achievement of overall access and social protection.

This paper is part of the PLOS Universal Health Coverage Collection.

Summary Points

1. The WHO has developed a post-2015 Global TB Strategy emphasizing that significant improvement to TB care and prevention will be impossible without the progressive realization of both universal health coverage and social protection. This paper discusses indicators and measurement approaches for both.
2. While access to high-quality TB diagnosis and treatment has improved dramatically in recent decades, there is still insufficient coverage, especially for correct diagnosis and treatment of multi-drug resistant TB.
3. Continued and expanded monitoring of effective coverage of TB diagnosis and treatment is needed, for which further improvements to existing surveillance systems are required.
4. Many households face severe financial hardship due to TB. Out-of-pocket costs for medical care, transport, and food are often high. However, income loss is the largest financial threat for TB-affected households.
5. Consequently, the financial risk protection target in the post-2015 Global TB Strategy—“No TB affected families experience catastrophic costs due to TB”—concerns all direct costs as well as income loss. This definition is more inclusive than the one conventionally used for “catastrophic health expenditure,” which concerns only direct medical costs.

     

Achieving global mortality reduction targets and universal health coverage: The impact of COVID-19

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.

Summary points

• The Coronavirus Disease 2019 (COVID-19) pandemic threatens progress toward a “grand convergence” in global health—universal reduction in deaths from infections and maternal and child health conditions to low levels—and toward achieving universal health coverage (UHC).
• Our analysis suggests that COVID-19 will exacerbate the difficulty of achieving grand convergence targets for tuberculosis (TB), maternal mortality, and, probably, for under-5 mortality. HIV targets are likely to be met.
• By 2035, our analysis suggests that the public sectors of low-income countries (LICs) would only be able to finance about a third of the costs of a package of 120 essential non-COVID-19 health interventions through domestic sources, unless the country increases significantly the priority assigned to the health sector; lower middle-income countries (LMICs) would likewise only be able to finance a little less than half.
• The likelihood of getting back on track for reaching grand convergence and UHC will depend on (i) how quickly COVID-19 vaccines can be deployed in LICs and LMICs; (ii) how much additional public sector health financing can be mobilized from external and domestic sources; and (iii) whether countries can rapidly strengthen and focus their health delivery systems.

     

Chapter 11: Genome-Wide Association Studies

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

What to Learn in This Chapter

• Basic genetic concepts that drive genome-wide association studies
• Genotyping technologies and common study designs
• Statistical concepts for GWAS analysis
• Replication, interpretation, and follow-up of association results

This article is part of the “Translational Bioinformatics” collection for PLOS Computational Biology.