PROTOCOL: Behavioral, information and monetary interventions to reduce energy consumption in households: A "living" systematic review.

This is the protocol for a Campbell systematic review. The objectives are as follows: Our proposed systematic review and meta-analysis will integrate the evidence available from all sources to answer the following questions: (1) to what extent can information, behavioral and monetary interventions reduce energy consumption of households in residential buildings? (average treatment effect of interventions) (2) what is the relative effectiveness of interventions? (account for heterogeneity in treatment effects across and within studies) (3) how effective are combinations of different interventions?

Systematic review and meta-analysis of ex-post evaluations on the effectiveness of carbon pricing.

Today, more than 70 carbon pricing schemes have been implemented around the globe, but their contributions to emissions reductions remains a subject of heated debate in science and policy. Here we assess the effectiveness of carbon pricing in reducing emissions using a rigorous, machine-learning assisted systematic review and meta-analysis. Based on 483 effect sizes extracted from 80 causal ex-post evaluations across 21 carbon pricing schemes, we find that introducing a carbon price has yielded immediate and substantial emission reductions for at least 17 of these policies, despite the low level of prices in most instances. Statistically significant emissions reductions range between -5% to -21% across the schemes (-4% to -15% after correcting for publication bias). Our study highlights critical evidence gaps with regard to dozens of unevaluated carbon pricing schemes and the price elasticity of emissions reductions. More rigorous synthesis of carbon pricing and other climate policies is required across a range of outcomes to advance our understanding of "what works" and accelerate learning on climate solutions in science and policy.

Missense3D-TM: Predicting the Effect of Missense Variants in Helical Transmembrane Protein Regions Using 3D Protein Structures.

Variant effect predictors assess if a substitution is pathogenic or benign. Most predictors, including those that are structure-based, are designed for globular proteins in aqueous environments and do not consider that the variant residue is located within the membrane. We report Missense3D-TM that provides a structure-based assessment of the impact of a missense variant located within a membrane. On a dataset of 2,078 pathogenic and 1,060 benign variants, spanning 711 proteins from 706 structures, Missense3D-TM achieved an accuracy of 66%, Mathews correlation coefficient of 0.37, sensitivity of 58% and specificity of 81%. Missense3D-TM performed similarly to mCSM-membrane: accuracy 66% vs 61% (p = 0.02) on an unbalanced test set and 70% vs 67% (p = 0.20) on a balanced test set. The Missense3D-TM website provides an analysis of the structural effects of the variant along with its predicted position within the membrane. The web server is available at http://missense3d.bc.ic.ac.uk/.

A common TMPRSS2 variant has a protective effect against severe COVID-19.

BACKGROUND: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection. METHODS: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry. RESULTS: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10-3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. CONCLUSION: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

Applying Human-Centered Design Principles to Digital Syndromic Surveillance at a Mass Gathering in India: Viewpoint.

In the wake of the COVID-19 pandemic, digital health tools have been deployed by governments around the world to advance clinical and population health objectives. Few interventions have been successful or have achieved sustainability or scale. In India, government agencies are proposing sweeping changes to India's digital health architecture. Underpinning these initiatives is the assumption that mobile health solutions will find near universal acceptance and uptake, though the observed reticence of clinicians to use electronic health records suggests otherwise. In this practice article, we describe our experience with implementing a digital surveillance tool at a large mass gathering, attended by nearly 30 million people. Deployed with limited resources and in a dynamic chaotic setting, the adherence to human-centered design principles resulted in near universal adoption and high end-user satisfaction. Through this use case, we share generalizable lessons in the importance of contextual relevance, stakeholder participation, customizability, and rapid iteration, while designing digital health tools for individuals or populations.

Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants.

The interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB ( http://missense3d.bc.ic.ac.uk/ ). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.

Social Technology: An Interdisciplinary Approach to Improving Care for Older Adults.

Population aging is a defining demographic reality of our era. It is associated with an increase in the societal burden of delivering care to older adults with chronic conditions or frailty. How to integrate global population aging and technology development to help address the growing demands for care facing many aging societies is both a challenge and an opportunity for innovation. We propose a social technology approach that promotes use of technologies to assist individuals, families, and communities to cope more effectively with the disabilities of older adults who can no longer live independently due to dementia, serious mental illness, and multiple chronic health problems. The main contributions of the social technology approach include: (1) fostering multidisciplinary collaboration among social scientists, engineers, and healthcare experts; (2) including ethical and humanistic standards in creating and evaluating innovations; (3) improving social systems through working with those who deliver, manage, and design older adult care services; (4) promoting social justice through social policy research and innovation, particularly for disadvantaged groups; (5) fostering social integration by creating age-friendly and intergenerational programs; and (6) seeking global benefit by identifying and generalizing best practices. As an emergent, experimental approach, social technology requires systematic evaluation in an iterative process to refine its relevance and uses in different local settings. By linking technological interventions to the social and cultural systems of older people, we aim to help technological advances become an organic part of the complex social world that supports and sustains care delivery to older adults in need.

Regulatory Sandboxes: A Cure for mHealth Pilotitis?

Mobile health (mHealth) and related digital health interventions in the past decade have not always scaled globally as anticipated earlier despite large investments by governments and philanthropic foundations. The implementation of digital health tools has suffered from 2 limitations: (1) the interventions commonly ignore the "law of amplification" that states that technology is most likely to succeed when it seeks to augment and not alter human behavior; and (2) end-user needs and clinical gaps are often poorly understood while designing solutions, contributing to a substantial decrease in usage, referred to as the "law of attrition" in eHealth. The COVID-19 pandemic has addressed the first of the 2 problems-technology solutions, such as telemedicine, that were struggling to find traction are now closely aligned with health-seeking behavior. The second problem (poorly designed solutions) persists, as demonstrated by a plethora of poorly designed epidemic prediction tools and digital contact-tracing apps, which were deployed at scale, around the world, with little validation. The pandemic has accelerated the Indian state's desire to build the nation's digital health ecosystem. We call for the inclusion of regulatory sandboxes, as successfully done in the fintech sector, to provide a real-world testing environment for mHealth solutions before deploying them at scale.

Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?

Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of the 2134 neutral variants are structurally damaging. Importantly, similar results are obtained when 1052 structures predicted using Phyre2 algorithm were used, even when the model shares low (<40%) sequence identity to the template. Thus, structure-based analysis of the effects of missense variants can be effectively applied to homology models. Our in-house pipeline, Missense3D, for structurally assessing missense variants was made available at http://www.sbg.bio.ic.ac.uk/~missense3d.

Reimagining Health Data Exchange: An Application Programming Interface-Enabled Roadmap for India.

In February 2018, the Government of India announced a massive public health insurance scheme extending coverage to 500 million citizens, in effect making it the world's largest insurance program. To meet this target, the government will rely on technology to effectively scale services, monitor quality, and ensure accountability. While India has seen great strides in informational technology development and outsourcing, cellular phone penetration, cloud computing, and financial technology, the digital health ecosystem is in its nascent stages and has been waiting for a catalyst to seed the system. This National Health Protection Scheme is expected to provide just this impetus for widespread adoption. However, health data in India are mostly not digitized. In the few instances that they are, the data are not standardized, not interoperable, and not readily accessible to clinicians, researchers, or policymakers. While such barriers to easy health information exchange are hardly unique to India, the greenfield nature of India's digital health infrastructure presents an excellent opportunity to avoid the pitfalls of complex, restrictive, digital health systems that have evolved elsewhere. We propose here a federated, patient-centric, application programming interface (API)-enabled health information ecosystem that leverages India's near-universal mobile phone penetration, universal availability of unique ID systems, and evolving privacy and data protection laws. It builds on global best practices and promotes the adoption of human-centered design principles, data minimization, and open standard APIs. The recommendations are the result of 18 months of deliberations with multiple stakeholders in India and the United States, including from academia, industry, and government.

Social and Spatial Clustering of People at Humanity's Largest Gathering.

Macroscopic behavior of scientific and societal systems results from the aggregation of microscopic behaviors of their constituent elements, but connecting the macroscopic with the microscopic in human behavior has traditionally been difficult. Manifestations of homophily, the notion that individuals tend to interact with others who resemble them, have been observed in many small and intermediate size settings. However, whether this behavior translates to truly macroscopic levels, and what its consequences may be, remains unknown. Here, we use call detail records (CDRs) to examine the population dynamics and manifestations of social and spatial homophily at a macroscopic level among the residents of 23 states of India at the Kumbh Mela, a 3-month-long Hindu festival. We estimate that the festival was attended by 61 million people, making it the largest gathering in the history of humanity. While we find strong overall evidence for both types of homophily for residents of different states, participants from low-representation states show considerably stronger propensity for both social and spatial homophily than those from high-representation states. These manifestations of homophily are amplified on crowded days, such as the peak day of the festival, which we estimate was attended by 25 million people. Our findings confirm that homophily, which here likely arises from social influence, permeates all scales of human behavior.

Task shifting in surgery: Lessons from an Indian Heart Hospital.

We present a case study that illustrates task shifting, the transfer of activities from senior to junior colleagues, in the context of cardiac surgery at the Narayana Health City Cardiac Hospital (NH) in India. The case discusses the factors driving the adoption of task shifting at NH and identifies the implications of task shifting for surgeon training, surgical capacity, and procedure costs. A comparison of the outcomes of two senior surgeons with similar experience, workload, and patient profiles--but varying in their level of task shifting--suggests that shifting of lower complexity tasks by senior surgeons to trained junior colleagues does not negatively impact in-hospital mortality and post-procedure length of stay. The study concludes with a discussion of task shifting's potential to improve access to affordable tertiary care in resource-constrained settings.

Ways of working at the interface between primary and specialist mental healthcare.

Ways of working at the interface between primary and specialist care are considered with discussion of the limits of available evidence and the potential for a new role for psychiatrists in providing supervision and consultation in novel models of care.

A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: clinical and radiographic features can help to differentiate benign from malignant lesions.

BACKGROUND: Malignant peripheral nerve sheath tumors are rare, and their aggressive nature mandates treatment in specialist centers. In contrast, benign peripheral nerve sheath tumors are common and are treated by a variety of specialist surgeons, including plastic surgeons. The authors aimed to detect features in the clinical presentation of peripheral nerve sheath tumors that point toward a diagnosis of malignant peripheral nerve sheath tumor and therefore prompt referral to a specialist center. METHODS: All histologically diagnosed primary peripheral nerve sheath tumors from January of 1995 to December of 2004 were identified from histopathology records. Notes were reviewed and analyzed with regard to symptoms, signs, radiology, electrophysiology, surgery, and pathology. Statistical comparisons used Fisher's exact test and the Mann-Whitney test. RESULTS: During the study period, 32 cases of malignant peripheral nerve sheath tumor in 30 patients were treated. Factors in the clinical evaluation that significantly predicted the presence of malignant peripheral nerve sheath tumor included site, large size, depth in relation to the deep fascia, short duration of symptoms, and pain. Magnetic resonance imaging and computed tomography were sensitive and specific ways of confirming the clinical diagnosis. Interestingly, schwannomata were harder to distinguish from malignant peripheral nerve sheath tumors both clinically and radiologically. CONCLUSIONS: The authors have reviewed their institutional experience of peripheral nerve sheath tumors over a 10-year period. Their results will help to focus clinical and radiologic investigation of patients presenting with these tumors.

Strategies that fit emerging markets.

It's no easy task to identify strategies for entering new international markets or to decide which countries to do business with. Many firms simply go with what they know-and fall far short of their goals. Part of the problem is that emerging markets have "institutional voids": They lack specialized intermediaries, regulatory systems, and contract-enforcing methods. These gaps have made it difficult for multinationals to succeed in developing nations; thus, many companies have resisted investing there. That may be a mistake. If Western companies don't come up with good strategies for engaging with emerging markets, they are unlikely to remain competitive. Many firms choose their markets and strategies for the wrong reasons, relying on everything from senior managers' gut feelings to the behaviors of rivals. Corporations also depend on composite indexes for help making decisions. But these analyses can be misleading; they don't account for vital information about the soft infrastructures in developing nations. A better approach is to understand institutional variations between countries. The best way to do this, the authors have found, is by using the five contexts framework. The five contexts are a country's political and social systems, its degree of openness, its product markets, its labor markets, and its capital markets. By asking a series of questions that pertain to each ofthe five areas, executives can map the institutional contexts of any nation. When companies match their strategies to each country's contexts, they can take advantage of a location's unique strengths. But first firms should weigh the benefits against the costs. If they find that the risks of adaptation are too great, they should try to change the contexts in which they operate or simply stay away.