Monoclonal Antibody Generation Using Single B Cell Screening for Treating Infectious Diseases.

The screening of antigen-specific B cells has been pivotal for biotherapeutic development for over four decades. Conventional antibody discovery strategies, including hybridoma technology and single B cell screening, remain widely used based on their simplicity, accessibility, and proven track record. Technological advances and the urgent demand for infectious disease applications have shifted paradigms in single B cell screening, resulting in increased throughput and decreased time and labor, ultimately enabling the rapid identification of monoclonal antibodies with desired biological and biophysical properties. Herein, we provide an overview of conventional and emergent single B cell screening approaches and highlight their potential strengths and weaknesses. We also detail the impact of innovative technologies-including miniaturization, microfluidics, multiplexing, and deep sequencing-on the recent identification of broadly neutralizing antibodies for infectious disease applications. Overall, the coronavirus disease 2019 (COVID-19) pandemic has reinvigorated efforts to improve the efficiency of monoclonal antibody discovery, resulting in the broad application of innovative antibody discovery methodologies for treating a myriad of infectious diseases and pathological conditions.

Relational One Health: A more-than-biomedical framework for more-than-human health, and lessons learned from Brazil, Ethiopia, and Israel.

The One Health conceptual framework envisions human, animal, and environmental health as interconnected. This framework has achieved remarkable progress in the control of zoonotic diseases, but it commonly neglects the environmental domain, implicitly prioritizes human life over the life of other beings, and fails to consider the political, cultural, social, historical, and economic contexts that shape the health of multispecies collectives. We have developed a novel theoretical framework, Relational One Health, which expands the boundaries of One Health, clearly defines the environmental domain, and provides an avenue for engagement with critical theory. We present a systematic literature review of One Health frameworks to demonstrate the novelty of Relational One Health, and to orient it with respect to other critically-engaged frameworks for One Health. Our results indicate that while Relational One Health complements several earlier frameworks, these other frameworks are either not intended for research, or for narrow sets of research questions. We then demonstrate the utility of Relational One Health for One Health research through case studies in Brazil, Israel, and Ethiopia. Empirical research which is grounded in theory can speak collectively, increasing the impact of individual studies and the field as a whole. One Health is uniquely poised to address several wicked challenges facing the 21st century-climate change, pandemics, neglected zoonoses, and biodiversity collapse-and a unifying theoretical tradition is key to generating the evidence needed to meet these challenges.

Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

Sex ratio at birth across 100 years in Sweden and risk of cardiovascular disease and all-cause mortality - a national register study.

The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from national registers. When the highest quartile of SRB was used as reference, a slightly increased risk of fatal CVD (HR 1.03 (95% confidence intervals, CI): 1.02-1.04), non-fatal CVD (HR 1.01; 95%CI: 1.01-1.02) and mortality (HR 1.02; 95%CI, 1.01-1.03) was found after full adjustments in men belonging to the lowest SRB quartile. A similar pattern was also found for fatal CHD in women. in the lowest SBR quartile compared to the highest, HR 1.03 (95%CI: 1.02-1.05). In conclusion, in birth cohorts with a relatively lower than expected number of males born, long-term adverse health effects were observed with slightly increased cardiovascular risk and total mortality at the population level. This could indicate that men belonging to so-called "culled cohorts" in a developed country during the 20th century are characterized by a slightly increased risk that could reflect negative early life influences and environmental exposures in pregnant women resulting in selective loss of male embryos or fetuses. In a public health perspective SRB could be of some importance to monitor as an aspect of birth statistics linked to relatively minor population health effects.

Oxylipin Dynamics Following A Single Bout of Yoga Exercise: A Pilot Randomized Controlled Trial Secondary Analysis.

Background: Yoga may promote health via a complex modulation of inflammation. Little is known about oxylipins, a class of circulating mediators involved in inflammation resolution. Objective: To explore the acute effects of yoga exercise on systemic levels of oxylipins. Methods: This is a secondary analysis of a three-arm (high-intensity-yoga: HY, n = 10); moderate-intensity-yoga: MY, n = 10; and no-intervention-control: CON, n = 10) pilot randomized controlled trial employing a single bout of yoga exercise. Blood samples (baseline and 4-timepoint post-intervention) were used for an unbiased metabolipidomic profiling analysis. Net Areas Under the Curve per oxylipin were evaluated for each group. Results: Lipoxin(LX)B4, prostaglandin(PG)D2, and resolvin(Rv)D3 exhibited a greater magnitude of change in HY compared with MY and CON. Conclusion: Findings inform the design of future trials exploring the acute effects of yoga exercise on oxylipins' systemic levels.

Using near misses, artificial intelligence, and machine learning to predict maritime incidents: A U.S. Coast Guard case study.

Two recent trends made this project possible: (1) The recognition that near misses can be predictors of future negative events and (2) enhanced artificial intelligence (AI) and machine learning (ML) tools that make data analytics accessible for many organizations. Increasingly, organizations are learning from prior incidents to improve safety and reduce accidents. The U.S. Coast Guard (USCG) uses a reporting system called the Marine Information for Safety and Law Enforcement (MISLE) database. Because many of the incidents that appear in this database are minor ones, this project initially focused on determining if near misses in MISLE could be predictors of future accidents. The analysis showed that recent near-miss counts are useful for predicting future serious casualties at the waterway level. Using this finding, a predictive AI/ML model was built for each waterway type by vessel combination. Random forest decision tree AI/ML models were used to identify waterways at significant accident risk. An R-based predictive model was designed to be run monthly, using data from prior months to make future predictions. The prediction models were trained on data from 2007 to 2022 and tested on 10 months of data from 2022, where prior months were added to test the next month. The overall accuracy of the predictions was 92%-99.9%, depending on model characteristics. The predictions of the models were considered accurate enough to be potentially useful in future prevention efforts for the USCG and may be generalizable to other industries that have near-miss data and a desire to identify and manage risks.

Movement of juvenile migratory birds from settlement to adulthood across the non-breeding range.

Among migratory vertebrates, high levels of fidelity to non-breeding sites during adulthood are common. If occupied sites vary in quality, strong site fidelity can have profound consequences for individual fitness and population demography. Given the prevalence of adult site fidelity, the regions of the non-breeding range to which juveniles first migrate, and the scale of any subsequent movements, are likely to be pivotal in shaping distributions and demographic processes across population ranges. However, inherent difficulties in tracking migratory individuals through early life mean that opportunities to quantify juvenile settlement and movements across non-breeding ranges, and the mechanisms involved, are extremely rare. Through long-term, range-wide resightings of hundreds of colour-marked individuals from their first migration to adulthood and the application of state-space models, we quantify levels of juvenile and adult regional-scale movements and distances at different life stages across the whole non-breeding distribution range in a migratory shorebird, the Black-tailed Godwit (Limosa limosa islandica). We show that the probability of individuals changing non-breeding regions (seven historical wintering regions spanning the Western Europe range) at all ages is very low (mean movement probability = 10.9% from first to subsequent winter, and 8.3% from first adult winter to later winters). Movement between regions was also low between autumn and winter of the same year for both juveniles (mean movement probability = 17.0%) and adults (10.4%). The great majority of non-breeding movements from the first autumn to adulthood were within regions and less than 100 km. The scarcity of regional-scale non-breeding movements from the first autumn to adulthood means that the factors influencing where juveniles settle will be key determinants of non-breeding distributions and of the rate and direction of changes in distributions.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

When Perfect Is the Enemy of Good: Results of a RAND Appropriateness Panel on Treat to Target in Asymptomatic IBD.

BACKGROUND: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. METHODS: Using the RAND/UCLA Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis (UC) and Crohn's disease (CD) and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected via anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. RESULTS: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in UC patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in CD patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age >65 years and a plan for pregnancy in the next year might influence decision-making in some settings. CONCLUSION: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Performance and Fatigue Patterns in Elite Cyclists During 6 h of Simulated Road Racing.

Fatigue resistance is vital for success in elite road cycling, as repeated, intense efforts challenge the athletes' ability to sustain peak performance throughout prolonged races. The present study combined recurrent performance testing and physiological measures during 6 h simulated racing with laboratory testing to investigate factors influencing fatigue resistance. Twelve male national elite cyclists (25 ± 3 years; 76 ± 6 kg and VO2max of 5.2 ± 0.5 L/min) completed incremental power and maximal fat oxidation tests. Subsequently, they underwent field testing with physiological measures and fatigue responses evaluated through peak sprint power and 5 km time trial (TT) testing after 0, 2, 4, and 6 h of exercise. Peak power declined from 1362 ± 176 W in first sprint to 1271 ± 152 W after 2 h (p < 0.01) and then stabilized. In contrast, TT mean power gradually declined from 412 ± 38 W in the first TT to 384 ± 41 W in the final trial, with individual losses ranging from 2% to 14% and moderately correlated (r2 = 0.45) to accumulated exercise time above lactate threshold. High carbohydrate intake (~90 g/h) maintained blood glucose levels, but post-TT [lactate] decreased from 15.1 ± 2 mM to 7.1 ± 2.3 mM, while fat oxidation increased from 0.7 ± 0.3 g/min at 0 h to 1.1 ± 0.1 g/min after 6 h. The study identifies fatigue patterns in national elite cyclists. Peak sprint power stabilized after an initial impairment from 0 to 2 h, while TT power gradually declined over the 6 h simulated race, with increased differentiation in fatigue responses among athletes.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

The genome sequence of the ten-spot ladybird, Adalia decempunctata (Linnaeus, 1758).

We present a genome assembly from an individual male Adalia decempunctata (the ten-spot ladybird; Arthropoda; Insecta; Coleoptera; Coccinellidae). The genome sequence is 489.4 megabases in span. Most of the assembly is scaffolded into 12 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 19.68 kilobases in length.

Birth weight and birth length affect future fracture risk differently in men and women.

We wanted to determine if there are any associations between birth factors and adult fracture risk. For women only, shorter birth length was associated with lower relative fracture risk. For women and men, individuals who were long at birth as well as tall in adulthood had a substantially higher relative fracture risk. PURPOSE: We aimed to examine associations between birth anthropometry and adult fracture risk and to investigate if developmental mismatch is associated with fracture risk. METHODS: We included 4635 participants (476 women and 4159 men; born 1921-1950) with hospital and national registry-based data on birth anthropometry and adult fractures (≥ 50 years). We tested associations by Cox proportional hazards regressions and present hazard ratios (HR) with 95% confidence intervals. RESULTS: In total, 1215 (26%) suffered ≥ 1 fracture during a mean observation period of 26 years. In women, unadjusted analyses indicated that both higher birth weight (HR 1.42 per kg (1.10-1.84)) and birth length (1.10 per cm (1.05-1.17)) were associated to higher adult fracture risk. After adjustment (year of birth and gestational age), statistical significance remained only for birth length, HR 1.10 per cm (1.04-1.17). For men, no associations were apparent. We found no associations between developmental mismatch (lower birth weight followed by higher adult weight) and adult fracture risk. However, for both sexes, being born tall and staying tall into adulthood was associated with a markedly higher (55-105%) relative fracture risk (HR women 2.09 (1.18-3.68), men 1.55 (1.19-2.03)) compared to being born short and remaining short in adulthood. CONCLUSION: In this study, being born shorter and lighter was associated with a lower risk for fractures ≥ 50 years in women. However, analyses indicated that tall adults who were also long at birth may be at markedly higher risk of fractures; this warrants further examinations.

Independent fitness consequences of group size variation in Verreaux's sifakas.

The costs and benefits of group living are also reflected in intraspecific variation in group size. Yet, little is known about general patterns of fitness consequences of this variation. We use demographic records collected over 25 years to determine how survival and reproductive success vary with group size in a Malagasy primate. We show that female reproductive rates of Verreaux's sifakas (Propithecus verreauxi) are not affected by total group size, but that they are supressed by the number of co-resident females, whereas mortality rates are significantly higher in larger groups. Neither annual rainfall nor the adult sex ratio have significant effects on birth and death rates. Hence, these sifakas enjoy the greatest net fitness benefits at small, and not the predicted intermediate group sizes. Thus, independent fitness proxies can vary independently as a function of group size as well as other factors, leading to deviations from optimal intermediate group sizes.

Global Surgery: The Challenges and Strategies to Win a War That Must Be Won.

Background: Modern science has conquered seas, land, and space. Although great strides have been made in technology and infectious diseases, global surgery, which was reborn in 2015, has not made much progress. The burden of surgical disease in low- and middle-income countries remains seemingly unconquerable, and its growth unstoppable. The myriad challenges in meeting the surgical needs of 5 billion people has intrigued the author. Methods: The author collected the views of plastic surgeons on sources and impediments to the scale-up of plastic surgery in low- and middle-income countries, as well as potential strategies for overcoming these obstacles. The author then performed a literature search reviewing the topics that arose from those discussions. The author proposes a strategy using plastic surgery as a model surgical discipline. Results: A root-cause analysis suggests that the Alma Ata Declaration, with its focus on primary healthcare, is the probable genesis of global surgery (GS) woes. The absence of a clear GS community leader and the fragmented nature of GS advocates who operate in multiple silos, without a clear unified goal, are the primary reasons GS advocates have achieved so little on the ground. Conclusions: Global surgery requires a business model to sustainably meet the surgical needs of the 5 billion people globally. The proposed and implemented strategies must meet rigorous criteria to ensure sustainability, as quick-fix solutions are counterproductive. The development of centers of excellence offers a viable solution to problems that must be addressed successfully.

Optimizing isometric midthigh pull testing protocols: impact on peak force and rate of force development and their association with jump performance.

BACKGROUND: Isometric strength testing is widely applied in sports science. However, we hypothesized that traditional testing procedures with a dual focus on both peak force (PF) and rate of force development (RFD) may compromise the true assessment of early RFD measures and lower the associative value towards vertical jump performance. METHODS: Therefore, PF and RFD were assessed for 47 active participants (24 females, 23 males) with a traditional isometric midthigh pull (IMTP) protocol ("push as hard and fast as possible" over 4 s) and an RFD-specific protocol ("push as fast as possible" over 2 s). IMTP measures were compared to squat (SJ), countermovement (CMJ) and drop-jump (DJ) performance. RESULTS: The RFD-specific protocol provided higher RFD (P<0.05) for time domains up to 100 ms but lower PF (P<0.001). Independent of protocol, SJ and CMJ performance displayed significant, but low-to-moderate correlations with all RFD measures (r=0.30-0.52) as well as PF (r=0.44), whereas DJ did not show any correlation. CONCLUSIONS: In conclusion, an RFD-specific protocol appears relevant for the assessment of RFD in the time domain up to 100 ms. However, the observed associations between RFD/PF measures and vertical jump performance remained low-to-moderate independent of the IMTP test protocol.

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

PURPOSE: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND METHODS: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Practical Guidance for Hemodynamic Assessment by Right Heart Catheterization in Management of Heart Failure.

Heart failure is a clinical syndrome characterized by the inability of the heart to meet the circulatory demands of the body without requiring an increase in intracardiac pressures at rest or with exertion. Hemodynamic parameters can be measured via right heart catheterization, which has an integral role in the full spectrum of heart failure: from ambulatory patients to those in cardiogenic shock, as well as patients being considered for left ventricular device therapy and heart transplantation. Hemodynamic data are critical for prompt recognition of clinical deterioration, assessment of prognosis, and guidance of treatment decisions. This review is a field guide for hemodynamic assessment, troubleshooting, and interpretation for clinicians treating patients with heart failure.