Improved protein structure prediction using potentials from deep learning.

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)-a blind assessment of the state of the field-AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7.

Expanding the Paradigm for Cardiovascular Palliative Care.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite medical advances, patients with CVD experience high morbidity and mortality rates, affecting their quality of life and death. Among CVD conditions, palliative care has been studied mostly in patients with heart failure, where palliative care interventions have been associated with improvements in patient-centered outcomes, including quality of life, end-of-life care, and health care use. Although palliative care is now incorporated into the American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines for heart failure, the role of palliative care for non-heart failure CVD remains uncertain. Across all causes of CVD, palliative care can play an important role in all domains of CVD care from initial diagnosis to terminal care. In addition to general cardiovascular palliative care practices applicable to all areas, disease-specific palliative care needs may warrant individualized palliative care models. In this review, we discuss the role of cardiovascular palliative care for ischemic heart disease, valvular disease, arrhythmias, peripheral artery disease, and adult congenital heart disease. Although there are multiple barriers to cardiovascular palliative care, we recommend a framework for studying and developing cardiovascular palliative care models to improve patient-centered goal-concordant care for this underserved patient population.

Sarcopenia and Cardiovascular Diseases.

Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.

Ethical and Equity Guidance for Transplant Programs Considering Thoracoabdominal Normothermic Regional Perfusion (TA-NRP) for Procurement of Hearts.

Donation after circulatory determination of death (DCDD) is an accepted practice in the United States, but heart procurement under these circumstances has been debated. Although the practice is experiencing a resurgence due to the recently completed trials using ex vivo perfusion systems, interest in thoracoabdominal normothermic regional perfusion (TA-NRP), wherein the organs are reanimated in situ prior to procurement, has raised many ethical questions. We outline practical, ethical, and equity considerations to ensure transplant programs make well-informed decisions about TA-NRP. We present a multidisciplinary analysis of the relevant ethical issues arising from DCDD-NRP heart procurement, including application of the Dead Donor Rule and the Uniform Definition of Death Act, and provide recommendations to facilitate ethical analysis and input from all interested parties. We also recommend informed consent, as distinct from typical "authorization," for cadaveric organ donation using TA-NRP.

Methane Emissions from Non-producing Oil and Gas Wells and the Potential Role of Seismic Activity: A Case Study in Northeast British Columbia, Canada.

Increasing seismic activity due to fluid injections for oil and gas production may be contributing to leakage along non-producing oil and gas wells and emitting methane, a potent greenhouse gas. However, the extent to which nearby seismicity may drive or exacerbate methane emissions and cause well integrity issues is unknown. Therefore, we analyze field evaluations at 448 non-producing oil and gas wells in Northeast British Columbia (NEBC) and geospatially analyze oil and gas well and fluid injection data alongside locations of 3515 earthquakes from 2001 to 2021 and 130 faults. Through analysis of ground and helicopter-based field evaluations of non-producing wells in NEBC, we show that methane emission rates of non-producing wells average at 8301 mg/h/well but vary by 10 orders of magnitude. We find that higher methane emission rates (milligrams of methane/h/well) are observed at wells with larger flowing pressures at the wellhead during completion (kPa) and with shorter distances (m) to earthquakes, particularly at plugged wells. These results imply that seismicity may increase the likelihood of non-producing well integrity issues and methane leakage, thereby also exacerbating groundwater contamination and environmental degradation risks.

What the 'greater good' excludes: Patients left behind by pre-operative COVID-19 screening in an Ethiopian town.

During the coronavirus disease 2019 (COVID-19) pandemic, bioethical analyses often emphasized population health and societal benefit. Hospital policies frequently focused on reducing risk of transmitting SARS-CoV-2 by restricting visitors; requiring protective equipment; and screening staff, patients and visitors. While restrictions can be burdensome, they are often justified as essential measures to protect the whole population against a virus with high rates of transmission, morbidity and mortality. Yet communities are not monolithic, and the impacts of these restrictions affect different groups differently. An ophthalmological unit outreach program in Ethiopia serves to illustrate. Pre-operative screening policies were designed to protect as many patients as possible but had adverse impacts on underserved communities. As this case study demonstrates, creating hospital policies that truly serve the good of the society may require a more holistic review of impacts on inequitably positioned communities.

Exertional desaturations after COVID-19: A case for PFO closure.

We present a case of a woman with past medical history notable for mild COVID-19 infection who presented with dyspnea on exertion, then developed progressively worsening exertional desaturations and was found to have a patent foramen ovale (PFO). Extensive cardiopulmonary testing revealed no clear alternate etiology for her symptoms. After much discussion, she underwent successful closure of the PFO with complete resolution of her symptoms and significantly improved exertional desaturation.

Cardiac point-of-care ultrasound publication trends.

INTRODUCTION: Cardiac point-of-care ultrasound (c-POCUS) is an increasingly implemented diagnostic tool with the potential to guide clinical management. We sought to characterize and analyze the existing c-POCUS literature with a focus on the temporal trends and differences across specialties. METHODS: A literature search for c-POCUS and related terms was conducted using Ovid (MEDLINE and Embase) and Web of Science databases through 2020. Eligible publications were classified by publication type and topic, author specialty, geographical region of senior author, and journal specialty. RESULTS: The initial search produced 1761 potential publications. A strict definition of c-POCUS yielded a final total of 574 cardiac POCUS manuscripts. A yearly increase in c-POCUS publications was observed. Nearly half of publications were original research (48.8%) followed by case report or series (22.8%). Most publications had an emergency medicine senior author (38.5%), followed by cardiology (20.8%), anesthesiology (12.5%), and critical care (12.5%). The proportion authored by emergency medicine and cardiologists has decreased over time while those by anesthesiology and critical care has generally increased, particularly over the last decade. First authorship demonstrated a similar trend. Articles were published in emergency medicine (24.4%) and cardiology journals (20.5%) with comparable frequency. CONCLUSION: The annual number of c-POCUS publications has steadily increased over time, reflecting the increased recognition and utilization of c-POCUS. This study can help inform clinicians of the current state of c-POCUS and augment the discussion surrounding barriers to continued adoption across all specialties.

Discharging to the Street: When Patients Refuse Medically Safer Options.

The ethical obligation to provide a reasonably safe discharge option from the inpatient setting is often confounded by the context of homelessness. Living without the security of stable housing is a known determinant of poor health, often complicating the safety of discharge and causing unnecessary readmission. But clinicians do not have significant control over unjust distributions of resources or inadequate societal investment in social services. While physicians may stretch inpatient stays beyond acute care need in the interest of their patients who are experiencing homelessness, they must also consider the implications of using an inpatient hospital bed for someone without the attendant level of medical need. Caring for patients in an inpatient setting when they no longer require acute care means fewer beds for acute care patients. And when a patient who is experiencing homelessness declines a medically safer option such as a skilled nursing facility, then clinicians may be faced with the sole option of discharge to the street, which raises troubling questions of nonmaleficence and social justice. Here we investigate the different forms of injustice that play out when patients are discharged to the street, and offer a map of the interwoven ethical responsibilities of clinicians, hospitals, and skilled nursing facilities.

Echocardiography in the Era of COVID-19: Lessons for the Future.

PURPOSE OF REVIEW: Poor cardiovascular outcomes are linked to COVID-19 in patients with or without prior cardiovascular disease or risk factors. Echocardiography, as a portable, versatile, and comprehensive imaging technique, has been on the frontlines. Yet sonographers and physician imagers are at increased risk of contracting or transmitting COVID-19. RECENT FINDINGS: Recent scientific statements incorporate triaging approaches to identify the appropriateness of imaging exam indications, coupled with triaging of indications. Additionally, focused protocols, procedures to reduce exposure, and point-of-care ultrasound play significant roles. Lessons learned during COVID-19 will apply to future pandemics. Echocardiography is a key diagnostic modality during pandemics in patients with or without prior cardiac diseases and risk factors. Attention to clinical questions, focused protocols, novel procedures, and future developments in imaging will contribute to safe and effective practice of echocardiography.

Overcoming catastrophic forgetting in neural networks.

The ability to learn tasks in a sequential fashion is crucial to the development of artificial intelligence. Until now neural networks have not been capable of this and it has been widely thought that catastrophic forgetting is an inevitable feature of connectionist models. We show that it is possible to overcome this limitation and train networks that can maintain expertise on tasks that they have not experienced for a long time. Our approach remembers old tasks by selectively slowing down learning on the weights important for those tasks. We demonstrate our approach is scalable and effective by solving a set of classification tasks based on a hand-written digit dataset and by learning several Atari 2600 games sequentially.

Advance care planning and palliative care in ACHD: the healthcare providers' perspective.

BACKGROUND: Advance care planning and palliative care are gaining recognition as critical care components for adults with CHD, yet these often do not occur. Study objectives were to evaluate ACHD providers' 1) comfort managing patients' physical symptoms and psychosocial needs and 2) perspectives on the decision/timing of advance care planning initiation and palliative care referral. METHODS: Cross-sectional study of ACHD providers. Six hypothetical patients were described in case format, followed by questions regarding provider comfort managing symptoms, initiating advance care planning, and palliative care referral. RESULTS: Fifty providers (72% physicians) completed surveys. Participants reported low levels of personal palliative care knowledge, without variation by gender, years in practice, or prior palliative care training. Providers appeared more comfortable managing physical symptoms and discussing prognosis than addressing psychosocial needs. Providers recognised advance directives as important, although the percentage who would initiate advance care planning ranged from 18 to 67% and referral to palliative care from 14 to 32%. Barriers and facilitators to discussing advance care planning with patients were identified. Over 20% indicated that advance care planning and end-of-life discussions are best initiated with the development of at least one life-threatening complication/hospitalisation. CONCLUSIONS: Providers noted high value in advance directives yet were themselves less likely to initiate advance care planning or refer to palliative care. This raises the critical questions of when, how, and by whom discussion of these important matters should be initiated and how best to support ACHD providers in these endeavours.

Protein structure prediction using multiple deep neural networks in the 13th Critical Assessment of Protein Structure Prediction (CASP13).

We describe AlphaFold, the protein structure prediction system that was entered by the group A7D in CASP13. Submissions were made by three free-modeling (FM) methods which combine the predictions of three neural networks. All three systems were guided by predictions of distances between pairs of residues produced by a neural network. Two systems assembled fragments produced by a generative neural network, one using scores from a network trained to regress GDT_TS. The third system shows that simple gradient descent on a properly constructed potential is able to perform on par with more expensive traditional search techniques and without requiring domain segmentation. In the CASP13 FM assessors' ranking by summed z-scores, this system scored highest with 68.3 vs 48.2 for the next closest group (an average GDT_TS of 61.4). The system produced high-accuracy structures (with GDT_TS scores of 70 or higher) for 11 out of 43 FM domains. Despite not explicitly using template information, the results in the template category were comparable to the best performing template-based methods.

Compassionate deactivation of ventricular assist devices in children: A survey of pediatric ventricular assist device clinicians' perspectives and practices.

OBJECTIVES: This study's objective was to investigate compassionate ventricular assist device deactivation (VADdeact) in children from the perspective of the pediatric heart failure provider. BACKGROUND: Pediatric VAD use is a standard therapy for advanced heart failure. Serious adverse events may affect relative benefit of continued support, leading to consideration of VADdeact. Perspectives and practices regarding VADdeact have been studied in adults but not in children. METHODS: A web-based anonymous survey of clinicians for pediatric VAD patients (<18 years) was sent to list-serves for the ISHLT Pediatric Council, the International Consortium of Circulatory Assist Clinicians Pediatric Taskforce, and the Pediatric Cardiac Intensivist Society. RESULTS: A total of 106 respondents met inclusion criteria of caring for pediatric VAD patients. Annual VAD volume per clinician ranged from <4 (33%) to >9 (20%). Seventy percent of respondents had performed VADdeact of a child. Response varied to VADdeact requests by parent or patient and was influenced by professional degree and region of practice. Except for the scenario of intractable suffering, no consensus on VADdeact appropriateness was reported. Age of child thought capable of making informed requests for VADdeact varied by subspecialty. The majority of respondents (62%) do not feel fully informed of relevant legal issues; 84% reported that professional society supported guidelines for VADdeact in children had utility. CONCLUSION: There is limited consensus regarding indications for VADdeact in children reported by pediatric VAD provider survey respondents. Knowledge gaps related to legal issues are evident; therefore, professional guidelines and educational resources related to pediatric VADdeact are needed.

Care Labor in VAD Therapy: Some Feminist Concerns.

Ventricular assist device (VAD) care offers a distinctive lens through which we can explore unjust gender norms. This is a resource-intensive intervention, one in which increasingly sophisticated technology brings with it the need for more long-term care. This care work is demanding, involving device maintenance, medication and appointment management, household work, and emotional support. Most patients eligible for receiving VADs are men, so it is not surprising that it is more often women who are responsible for the care of patients with VADs. Still, there is room to question why so much of this labor is expected of and taken on by female caregivers, when it could be shared with male caregivers and even patients themselves. To the extent that gender difference in the distribution of this labor is avoidable and inequitable, it becomes in part a disparity resulting from unjust social norms. In order to unpack some of this injustice, the authors utilize empiric data and theoretical work in feminist ethics to articulate some of the mechanisms of the gender disparity in VAD care labor and to offer communitarian decision-making and redistribution of care labor as potential routes toward greater justice for women with respect to VAD therapy.

Landowner Perceptions of Payments for Nature Conservation on Private Land.

Private land conservation (PLC) programs often provide financial incentives to motivate and enable landowners to engage in conservation. However, few studies have explored the psychological and management impacts of these incentives. We interviewed 50 landowners in Tasmania, Australia who were engaged in incentivised or nonincentivised PLC programs. Landowners who received incentives were paid to either protect private land through creating a conservation covenant (a legal deed restricting land uses) or engage in a specific stewardship activity (e.g., planting trees). Most landowners who received payments to create covenants stated that they would not have done so without the payment. However, landowners, including those who have purchased or inherited covenanted properties, also indicated that neither these payments, nor the conservation covenant made any significant impact on how they managed the land. Covenant incentives did not improve attitudes towards conservation or conservationists. In contrast, most landowners receiving stewardship payments reported that these payments enabled the conservation actions they valued, helped build relationships and promoted favorable attitudes towards conservation. Contextual factors that influenced the impact of financial incentives on conservation action included the quality of relationship between landowners and stewardship officers, availability of private funds for conservation, and multigenerational aspirations. Our research identifies some of the intended and unintended impacts of financial incentives and describes how a fuller understanding of the motivations, identities, and aspirations of landowners may lead to the design of more socially resilient and ecologically effective PLC programs.

Remaining longevity and evidence of failure of cardiac implantable electrophysiology devices recovered from funeral homes.

BACKGROUND: Given the prohibitive cost of pacemakers and defibrillators for medically underserved patients in low-income countries, these devices are sometimes recovered from funeral homes for charitable reimplantation. Many devices are implanted near the end of the patients' lives, meaning that recovered devices from funeral homes have the potential for significant remaining longevity. METHODS: After sending letters asking funeral directors in the Philadelphia area to donate explanted pacemakers and defibrillators, 78 devices were recovered. Sixty-seven of these devices were successfully interrogated, and 64 devices reported estimates of remaining battery life in years. Twenty-one defibrillators were also interrogated for evidence of failure. RESULTS: Twenty-two percent of the 64 devices had greater than 4 years of longevity. Fourteen percent of the devices had between 1 and 4 years of longevity, and the remaining 64% had less than 1 year of remaining battery life. We found no evidence from 21 recovered defibrillators that the patient's cause of death was because of defibrillator failure. In almost half (10/21) of the defibrillators, however, the arrhythmia logs were nondecipherable given the entire log was replaced by episodes of signal noise likely occurring after death. CONCLUSIONS: A significant percentage of devices explanted in funeral homes have suitable remaining battery life for reuse. While no evidence of defibrillator device failure could be found, the analysis was limited by postmortem signal artifact, which may preclude accurate assessment of rates of failure in devices explanted postmortem.

Putting the "Informed" in the informed consent process for implantable cardioverter-defibrillators: Addressing the needs of the elderly patient.

Implantable cardioverter defibrillator (ICD) management complexities challenge the ethos of fully informed consent, particularly for the typically multimorbid elderly patient considering the device for primary prevention. The Heart Rhythm Society recommends providers include discussion on the potential need for later device deactivation or nonreplacement at the time of first implant, and to revisit this at appropriate intervals. The initial consent procedure could meet this standard by incorporating the future need to discuss further such issues when the recipient's clinical condition changes to such an extent that defibrillation would no longer be beneficial. At the time of obtaining consent, some patients may lack the will or capacity to make medically complex decisions when it would be necessary for healthcare surrogate decision-makers to contribute to this process. Ensuring an appropriate level of understanding and response may be enhanced by the use of information and decision aids. With improved communication regarding the nuances of ICD therapy, device eligible patients, and those close to them, will be empowered with a better understanding of the nature, benefits, and risks of ICD implantation, allowing them to make treatment decisions consistent with their values.

Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS).

Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases of thyroid carcinoma have been reported in children with PHTS. We conducted a retrospective, single-centered study including children and adolescents with a molecularly proven diagnosis of PTEN. Our cohort consists of 16 patients, with a mean age at diagnosis PHTS of 5.7 years. Twelve of 16 cases exhibited thyroid abnormalities (75%). In seven patients, thyroid abnormalities were already present at first ultrasound screening, in five cases they occurred during follow-up. Eight patients underwent thyroidectomy. Histopathology included nodular goiter, follicular adenoma, papillary microcarcinoma in a boy of six and follicular carcinoma in a girl of 13 years. Two patients had autoimmune thyroid disease. CONCLUSION: Thyroid disease is common in children with PHTS. Physicians caring for patients with early thyroid abnormalities and additional syndromal features should be aware of PHTS as a potentially underlying disorder. Ultrasound screening should be performed immediately after diagnosis of PHTS and repeated yearly or more frequently. Because of possible early cancer development, we recommend early surgical intervention in the form of total thyroidectomy in cases of suspicious ultrasound findings. What is Known: • PHTS patients are at high risk of developing benign and malignant tumors. • Individual cases of thyroid carcinoma in children have been reported. What is New: • Thyroid disease is even more common in children with PHTS (75%) than previously expected. • Frequently thyroid disease is the first organ pathology requiring diagnostic workup and therefore children with PHTS should be examined for thyroid disease right after diagnosis and receive follow-up on a regular basis throughout life.

PREVALENCE OF FOVEOLAR LUCENCY WITH DIFFERENT GAS TAMPONADES IN SURGICALLY CLOSED MACULAR HOLES ASSESSED BY SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the prevalence of foveolar lucency (FL) in surgically closed macular holes by spectral domain optical coherence tomography. METHODS: One hundred forty-two eyes of 132 patients underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade in a 60-month time frame. Anatomical success and FL rates assessed by spectral domain optical coherence tomography, mean preoperative, and postoperative best-measured visual acuity and surgical details were retrospectively analyzed. RESULTS: Spectral domain optical coherence tomography confirmed closed holes with FL in 33.7% (34/101) of eyes at 1 month, 7.3% (9/123) at 3 months, 4.6% (6/129) at 6 months, and 3% (4/133) at 12 months. Prevalence of FL in closed holes at Month 1 was lower in C3F8-treated eyes (9.5%, 2/21) compared with C2F6 (40.9%, 18/44, P = 0.03) and SF6-treated eyes (38.9%, 14/36, P = 0.05). No differences were observed at Month 3. No differences in best-measured visual acuity change were observed between closed holes with or without FL at Month 1 (-0.14 ± 0.19 vs. -0.11 ± 0.23, P = 0.48) or any of the other time points. CONCLUSION: Temporary FL is a highly prevalent feature in successfully closed macular holes. Eyes treated with C3F8 gas had lower rates of FL at Month 1 than C2F6 and SF6-treated eyes. The presence of FL in closed holes does not seem to have any effect on the visual outcomes.