bluuebunny/crossref_metadata_2025 huggingface dataset:
Courts, Constitutionalism, and State Capacity: A Preliminary Inquiry
Authors: Khosla Madhav , Tushnet Mark
Published: May 2022

Modern constitutional theory deals almost exclusively with the mechanisms for controlling the exercise of public power. In particular, the focus of constitutional scholars lies in explaining and justifying how courts can effectively keep the exercise of public power within bounds. But there is little point in worrying about the excesses of government power when the government lacks the capacity to get things done in the first place. In this Article, we examine relations between the courts, constitutionalism, and state capacity other than through limiting state power. Through a series of case studies, we suggest how courts confront the problem of state building, and how the question of state capacity informs constitutional doctrine. Our studies consist of litigation over life-saving medication in Brazil, “engagement” remedies in South Africa, the problem of pretrial detention in India, and the validity of India’s recent biometric identification project. As we show, state capacity is a crucial variable in the development of constitutional doctrine—and while engaging with the issue of state capacity, courts often play a role in facilitating its expansion. The case studies identify a number of mechanisms that courts use to encourage capacity development: providing incentives to enhance capacity, guiding and directing the state to perform specific actions, compensating for weak capacity by absorbing the problem, and endorsing measures that purport to increase capacity. We then offer an expressly idealized model by which courts can negotiate capacity-related concerns. Courts can, in certain instances, respond to the problem of state capacity through weak-form, dialogic, experimentalist forms of review. The precise role that courts can and should play in this regard remains to be fully studied, but focusing on the question of state capacity allows us to better explain contemporary constitutional doctrine in several jurisdictions, and highlights the challenges involved in at once creating and limiting state power.
DenVar: density-based variation analysis of multiplex imaging data
Authors: Seal Souvik , Vu Thao , Ghosh Tusharkanti , Wrobel Julia , Ghosh Debashis
Published: May 2022

Multiplex imaging platforms have become popular for studying complex single-cell biology in the tumor microenvironment (TME) of cancer subjects. Studying the intensity of the proteins that regulate important cell-functions becomes extremely crucial for subject-specific assessment of risks. The conventional approach requires selection of two thresholds, one to define the cells of the TME as positive or negative for a particular protein, and the other to classify the subjects based on the proportion of the positive cells. We present a threshold-free approach in which distance between a pair of subjects is computed based on the probability density of the protein in their TMEs. The distance matrix can either be used to classify the subjects into meaningful groups or can directly be used in a kernel machine regression framework for testing association with clinical outcomes. The method gets rid of the subjectivity bias of the thresholding-based approach, enabling easier but interpretable analysis. We analyze a lung cancer dataset, finding the difference in the density of protein HLA-DR to be significantly associated with the overall survival and a triple-negative breast cancer dataset, analyzing the effects of multiple proteins on survival and recurrence. The reliability of our method is demonstrated through extensive simulation studies.

Availability and implementation

The associated R package can be found here, https://github.com/sealx017/DenVar.

Supplementary information

Supplementary data are available at Bioinformatics Advances online.
Using the UK Biobank as a global reference of worldwide populations: application to measuring ancestry diversity from GWAS summary statistics
Authors: Privé Florian
Published: May 2022

Motivation

Measuring genetic diversity is an important problem because increasing genetic diversity is a key to making new genetic discoveries, while also being a major source of confounding to be aware of in genetics studies.

Results

Using the UK Biobank data, a prospective cohort study with deep genetic and phenotypic data collected on almost 500 000 individuals from across the UK, we carefully define 21 distinct ancestry groups from all four corners of the world. These ancestry groups can serve as a global reference of worldwide populations, with a handful of applications. Here, we develop a method that uses allele frequencies and principal components derived from these ancestry groups to effectively measure ancestry proportions from allele frequencies of any genetic dataset.

Availability and implementation

This method is implemented in function snp_ancestry_summary of R package bigsnpr.

Supplementary information

Supplementary data are available at Bioinformatics online.
Automated detection of low ejection fraction from a one-lead electrocardiogram: application of an AI algorithm to an electrocardiogram-enabled Digital Stethoscope
Authors: Attia Zachi I , Dugan Jennifer , Rideout Adam , Maidens John N , Venkatraman Subramaniam , Guo Ling , Noseworthy Peter A , Pellikka Patricia A , Pham Steve L , Kapa Suraj , Friedman Paul A , Lopez-Jimenez Francisco
Published: May 2022

Aims

Electrocardiogram (ECG)-enabled stethoscope (ECG-Scope) acquires a single-lead ECGs during cardiac auscultation and may facilitate real-time screening for pathologies not routinely identified by cardiac auscultation alone. We previously demonstrated an artificial intelligence (AI) algorithm can identify left ventricular dysfunction (LVSD) [defined as ejection fraction (EF) ≤ 40%] with an area under the curve (AUC) of 0.91 using a 12-lead ECG.

Methods and results

One hundred patients referred for clinically indicated echocardiography were prospectively recruited. ECG-Scope recordings with the patient supine and sitting were obtained in multiple electrode locations at the time of the echocardiogram. The AI algorithm for the detection of LVSD was retrained using single leads from ECG-12 and validated against ECG-Scope to determine accuracy for low EF detection (≤35%, <40%, or <50%). We evaluated the algorithm with respect to body position and lead location. Amongst 100 patients (aged 61.3 ± 13.8; 61% male, BMI: 30.0 ± 5.4), eight had EF≤40%, and six had EF 40–50%. The best single recording position was V2 with the patient supine [AUC: 0.88 (CI: 0.80–0.97) for EF≤35%, 0.85 (CI: 0.75–0.95) for EF≤40%, and 0.81 (CI: 0.71–0.90) for EF < 50%]. When using an AI model to select the recording automatically, AUC was 0.91 (CI: 0.84–0.97) for EF≤35%, 0.89 (CI: 0.83–0.96) for EF≤40%, and 0.84 (CI: 0.73–0.94) for EF < 50%.

Conclusion

An AI algorithm applied to an ECG-enabled stethoscope recording in standard auscultation positions reliably detected the presence of a low EF in this prospective study of patients referred for echocardiography. The ability to screen patients with a possible low EF during routine physical examination may facilitate rapid detection of LVSD.
AZI2 positively regulates the induction of type I interferon in influenza-trigger pediatric pneumonia
Authors: Wei Meili , Zheng Yanfei , Xu Jing , Sun Qiwei
Published: May 2022

5-azacytidine-induced protein 2 (AZI2) is known to have a crucial role in antiviral innate immunity. This study aims to explore the roles of AZI2 in influenza-trigger pediatric pneumonia and its molecular mechanism. qPCR and immunoblotting assays were used to determine the levels of target genes and proteins. The lung infection mouse model was established by using PR8 H1N1 virus in AZI2 germline knockout (AZI2−/−) and wild-type (WT) mice. In addition, HEK293T cell-based luciferase reporter assays were used to investigate the regulatory effects of AZI2 on type I interferon. Immune precipitation and immunofluorescence staining were used to evaluate the interactions between AZI2 and TANK binding kinase 1 (TBK1). We observed an elevation in the expressions of IFN-I and AZI2 in peripheral blood mononuclear cells from the pneumonia patients with mild symptoms. Interestingly, AZI2 deficiency deteriorated the influenza-induced pathological symptoms in the lung as well as reduced the survival rate. It was further showed that AZI2 positively regulated the expressions of type I interferon, inflammatory cytokines, and IFN production-related genes. The molecular mechanism data revealed that AZI2 regulated the interactions between TBK1 and TANK. In summary, AZI2 positively regulates type I interferon production in influenza-induced pediatric pneumonia by promoting the interactions between TBK1 and TANK.
Microbiota manipulation through the secretion of effector proteins is fundamental to the wealth of lifestyles in the fungal kingdom
Authors: Snelders Nick C , Rovenich Hanna , Thomma Bart P H J
Published: May 2022

Fungi are well-known decomposers of organic matter that thrive in virtually any environment on Earth where they encounter wealths of other microbes. Some fungi evolved symbiotic lifestyles, including pathogens and mutualists, that have mostly been studied in binary interactions with their hosts. However, we now appreciate that such interactions are greatly influenced by the ecological context in which they take place. While establishing their symbioses, fungi not only interact with their hosts but also with the host-associated microbiota. Thus, they target the host and its associated microbiota as a single holobiont. Recent studies have shown that fungal pathogens manipulate the host microbiota by means of secreted effector proteins with selective antimicrobial activity to stimulate disease development. In this review, we discuss the ecological contexts in which such effector-mediated microbiota manipulation is relevant for the fungal lifestyle and argue that this is not only relevant for pathogens of plants and animals but also beneficial in virtually any niche where fungi occur. Moreover, we reason that effector-mediated microbiota manipulation likely evolved already in fungal ancestors that encountered microbial competition long before symbiosis with land plants and mammalian animals evolved. Thus, we claim that effector-mediated microbiota manipulation is fundamental to fungal biology.
Male Bowhead Whale Reproductive Histories Inferred from Baleen Testosterone and Stable Isotopes
Authors: Hunt Kathleen E , Buck C Loren , Ferguson Steven H , Fernández Ajo Alejandro , Heide-Jørgensen Mads Peter , Matthews Cory J D
Published: May 2022

Synopsis

Male mammals of seasonally reproducing species typically have annual testosterone (T) cycles, with T usually peaking during the breeding season, but occurrence of such cycles in male mysticete whales has been difficult to confirm. Baleen, a keratinized filter-feeding apparatus of mysticetes, incorporates hormones as it grows, such that a single baleen plate can record years of endocrine history with sufficient temporal resolution to discern seasonal patterns. We analyzed patterns of T every 2 cm across the full length of baleen plates from nine male bowhead whales (Balaena mysticetus) to investigate occurrence and regularity of T cycles and potential inferences about timing of breeding season, sexual maturation, and reproductive senescence. Baleen specimens ranged from 181–330 cm in length, representing an estimated 11 years (smallest whale) to 22 years (largest whale) of continuous baleen growth, as indicated by annual cycles in stable isotopes. All baleen specimens contained regularly spaced areas of high T content (T peaks) confirmed by time series analysis to be cyclic, with periods matching annual stable isotope cycles of the same individuals. In 8 of the 9 whales, T peaks preceded putative summer isotope peaks by a mean of 2.8 months, suggesting a mating season in late winter / early spring. The only exception to this pattern was the smallest and youngest male, which had T peaks synchronous with isotope peaks. This smallest, youngest whale also did not have T peaks in the first half of the plate, suggesting initiation of T cycling during the period of baleen growth. Linear mixed effect models suggest that whale age influences T concentrations, with the two largest and oldest males exhibiting a dramatic decline in T peak concentration across the period of baleen growth. Overall, these patterns are consistent with onset of sexual maturity in younger males and possible reproductive senescence in older males. We conclude that adult male bowheads undergo annual T cycles, and that analyses of T in baleen may enable investigation of reproductive seasonality, timing of the breeding season, and life history of male whales.
Cellular goore game with application to finding maximum clique in social networks
Authors: Khomami Mohammad Mehdi Daliri , Meybodi Mohammad Reza , Ameri Reyhaneh
Published: May 2022

The goore game (GG) is a model for collective decision making under uncertainty, which can be used as a tool for stochastic optimization of a discrete variable function. The GG has a fascinating property that can be resolved in a distributed manner with no intercommunication between the players. The game has found applications in many network applications, including sensor networks, quality-of-service routing, and social networks. In this paper, we introduce an extension of GG called cellular goore game (CGG) for the first time. The CGG is a network of GGs. In this network, each node (or subset of nodes in the network) plays the rule of referees, each of which participates in a GG with its neighboring players (voters) at any time. Like in GG, each player independently selects its optimal action between two available actions based on their gains and losses received from its adjacent referee. Players in CGG know nothing about how other players are playing or even how/why they are rewarded/penalized. The potential of the CGG is shown by providing an algorithm for finding a maximum clique in social networks. Our research provides the first-time study of the CGG for finding a maximum clique in graphs. The performance of the CGG-based algorithm for finding maximum clique is studied on the standard clique benchmark called DIMACS by several experiments. The obtained result shows that the CGG-based algorithm is superior to the existing algorithms in terms of finding maximum clique size and time.
Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed diffuse intrinsic pontine glioma: A Children’s Oncology Group phase I consortium study
Authors: Mueller Sabine , Cooney Tabitha , Yang Xiaodong , Pal Sharmistha , Ermoian Ralph , Gajjar Amar , Liu Xiaowei , Prem Komal , Minard Charles G , Reid Joel M , Nelson Marvin , Haas-Kogan Daphne , Fox Elizabeth , Weigel Brenda J
Published: May 2022

Background

Children with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress.

Methods

Using a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage.

Results

A total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3–21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control.

Conclusion

Adavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.
Dynamic occupancy models reveal Black-billed and Yellow-billed Cuckoos have high rates of turnover during the breeding season
Authors: Johnson Claire A , Benson Thomas J
Published: May 2022

Understanding the conservation needs of rare and hard-to-detect species becomes even more difficult when a species is highly mobile. Black-billed Cuckoos (Coccyzus erythropthalmus) and Yellow-billed Cuckoos (Coccyzus americanus) have experienced extensive range-wide population declines over the last several decades. Low detection probability has made it hard to determine causes of declines and resulted in poorly supported population and trend estimates. However, given evidence that cuckoos make wide-ranging movements during the breeding season, it may be necessary to address issues of both low vocalization rate and availability for detection to better understand these cryptic species. We performed passive and call-broadcast surveys for cuckoos at 41 sites across northern Illinois in 2019 and 2020. We examined the influence of call broadcast and temporal and environmental covariates on detection probability and how habitat covariates affected occupancy, immigration, and emigration both within and among sites. Individual detection probability increased substantially using call broadcasts (12 and 6 times for Black-billed and Yellow-billed Cuckoos, respectively) and detection increased with temperature. Black-billed Cuckoo detection probability also varied temporally, being lowest in the middle of the breeding season. We found strong support for turnover within sites during the breeding season, indicating maintenance of large home ranges, as well as among sites (average emigration probability of 86% and 47% for Black-billed and Yellow-billed Cuckoos, respectively). Black-billed Cuckoos were more likely to use open, shrubby sites and Yellow-billed Cuckoos to use sites with older successional habitat. While turnover rate was affected by habitat covariates, these species’ reliance on ephemeral insect abundance may ultimately be driving occupancy dynamics. Our results suggest that broadcasts are essential for effectively monitoring these cuckoos, but also imply the need to move towards coordinating management at broader spatial scales for these highly mobile species.
Haemosporidian parasite diversity and prevalence in the songbird genusJuncoacross Central and North America
Authors: Martínez-Renau Ester , Rojas-Estévez Natalia , Friis Guillermo , Hernández-Montoya Julio C , Elizondo Pablo , Milá Borja
Published: May 2022

The evolution of host–parasite interactions as host lineages colonize new geographic regions and diversify over evolutionary time is poorly understood. To assess whether haemosporidian parasite diversity has changed during the diversification of an avian host, we surveyed the diversity and prevalence of blood parasite lineages (genera Plasmodium, Haemoproteus, and Leucocytozoon) across the range of the songbird genus Junco, which has diversified recently as it recolonized North America following the last glacial maximum ~18,000 years ago. We report the diversity and prevalence of parasites in junco taxa sampled from Costa Rica to Canada, and examine the influence of local avian species richness in the prevalence and diversity of parasites in junco samples. We screened for parasites in each individual by sequencing a fragment of their cytochrome b gene, identifying the different lineages, and quantifying the prevalence per junco taxon and locality. Of 304 juncos sampled, 178 tested positive for 1 or more parasite genera (58.5% overall prevalence). We found high parasite diversity in genera Haemoproteus and Leucocytozoon and much lower diversity in Plasmodium. Among the 63 parasite lineages detected, 32 of which have not been previously described, we found generalist lineages with widespread but low prevalence in Junco, but also some that appear to have remained specialized on this genus as it diversified across North America over thousands of years. Our results suggest a range of parasitic strategies, ranging from specialized to generalist lineages within single parasite genera.
History and best practices of captive bolt euthanasia for swine
Authors: Anderson Karly N , Deen John , Karczewski Jerry , Zhitnitskiy Perle E , Vogel Kurt D
Published: May 2022

The definition of animal welfare includes how an animal dies. As such, euthanasia is intrinsically linked to animal welfare, and ensuring a good death through effective, safe, and validated practices is a critical piece of promoting positive animal welfare. The objective of this review is to provide a better understanding of the literature on the euthanasia of swine via penetrating captive bolt (PCB) and nonpenetrating captive bolt (NPCB), as well as a history of captive bolt use, and indicators of sensibility and insensibility. To do this, we performed a systematic review that included 30 peer-reviewed articles and 17 other publications. NPCB devices have been validated as an effective single-step euthanasia method for neonatal and preweaning swine, as well as a two-step euthanasia method for nursery swine. PCB devices have been validated as an effective euthanasia method for nursery and market swine up to 120 kg, but further investigation is required for the use of captive bolt devices on mature breeding sows and boars.
Polyclonal antibody preparations from avian origin as a feed additive to beef cattle: ruminal fermentation during the step-up transition diets
Authors: Silva Gleise M , Podversich Federico , Schulmeister Tessa M , Santos Erick R S , Sanford Carla , Siqueira Michelle C B , DiLorenzo Nicolas
Published: May 2022

This study investigated the effects of feeding an avian-derived polyclonal antibody preparation (PAP; CAMAS, Inc.) against Streptococcus bovis, Fusobacterium necrophorum, and lipopolysaccharides (40%, 35%, and 25% of the preparation, respectively) on ruminal fermentation [pH, ammonia-N (NH3-N), lactate, and volatile fatty acids (VFA)] of beef steers during a 21-d step-up diet adaptation. Eight ruminally cannulated Angus crossbred beef steers (658 ± 79 kg of body weight) were assigned in a crossover design to be transitioned from a diet containing ad libitum bermudagrass hay [Cynodon dactylon (L.) Pers.] plus 0.45 kg/d (as fed) of molasses with 0 (CON) or 3 g of PAP (PAP) to a high-grain diet. Transition consisted of three 7-d steps of increased inclusion of cracked corn (35%, 60%, and 82% of the diet DM for STEP1, STEP2, and STEP3, respectively). On each transition day and 7 d after STEP3 (STEP3-7d), ruminal fluid samples were obtained every 3 h for 24 h. Feeding 3 g of PAP daily increased (P < 0.01) average ruminal pH during STEP3 compared with CON steers (5.6 vs. 5.4 ± 0.05, respectively). During STEP1, NH3-N concentration was greater (P < 0.01; 9.4 vs. 6.8 ± 0.74 mM, respectively), and time (min/d) and area (time × pH) of ruminal pH below or equal to 5.2 was lesser (P ≤ 0.03) for steers consuming PAP compared with steers assigned to CON treatment (33.4 vs. 73.3 ± 21.7 min/d and 187.4 vs. 406.3 ± 119.7 min × pH/d, respectively). Steers consuming PAP had greater acetate:propionate ratio at 0, 3, and 6 h relative to diet change compared with CON (2.42, 2.35, 2.29 vs. 1.66, 1.79, and 1.72 ± 0.17, respectively), whereas butyrate molar proportions increased (P = 0.02; 17.1 vs. 11 ± 1.58 mol/100 mol for CON and PAP, respectively) when PAP was not fed at STEP2. Total ruminal lactate concentrations were not affected by PAP feeding (P > 0.11). In conclusion, feeding 3 g/d of polyclonal antibody preparation against S. bovis, F. necrophorum, and lipopolysaccharides was effective in increasing ruminal pH, A:P ratio, and NH3-N concentrations, possibly attenuating the risks of ruminal acidosis in steers during the step-up transition from forage to high-grain diets.
Competition for dominance within replicating quasispecies during prolonged SARS-CoV-2 infection in an immunocompromised host
Authors: Caccuri Francesca , Messali Serena , Bortolotti Daria , Di Silvestre Dario , De Palma Antonella , Cattaneo Chiara , Bertelli Anna , Zani Alberto , Milanesi Maria , Giovanetti Marta , Campisi Giovanni , Gentili Valentina , Bugatti Antonella , Filippini Federica , Scaltriti Erika , Pongolini Stefano , Tucci Alessandra , Fiorentini Simona , d’Ursi Pasqualina , Ciccozzi Massimo , Mauri Pierluigi , Rizzo Roberta , Caruso Arnaldo
Published: May 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge for their capability to better adapt to the human host aimed and enhance human-to-human transmission. Mutations in spike largely contributed to adaptation. Viral persistence is a prerequisite for intra-host virus evolution, and this likely occurred in immunocompromised patients who allow intra-host long-term viral replication. The underlying mechanism leading to the emergence of variants during viral persistence in the immunocompromised host is still unknown. Here, we show the existence of an ensemble of minor mutants in the early biological samples obtained from an immunocompromised patient and their dynamic interplay with the master mutant during a persistent and productive long-term infection. In particular, after 222 days of active viral replication, the original master mutant, named MB610, was replaced by a minor quasispecies (MB61222) expressing two critical mutations in spike, namely Q493K and N501T. Isolation of the two viruses allowed us to show that MB61222 entry into target cells occurred mainly by the fusion at the plasma membrane (PM), whereas endocytosis characterized the entry mechanism used by MB610. Interestingly, coinfection of two human cell lines of different origin with the SARS-CoV-2 isolates highlighted the early and dramatic predominance of MB61222 over MB610 replication. This finding may be explained by a faster replicative activity of MB61222 as compared to MB610 as well as by the capability of MB61222 to induce peculiar viral RNA-sensing mechanisms leading to an increased production of interferons (IFNs) and, in particular, of IFN-induced transmembrane protein 1 (IFITM1) and IFITM2. Indeed, it has been recently shown that IFITM2 is able to restrict SARS-CoV-2 entry occurring by endocytosis. In this regard, MB61222 may escape the antiviral activity of IFITMs by using the PM fusion pathway for entry into the target cell, whereas MB610 cannot escape this host antiviral response during MB61222 coinfection, since it has endocytosis as the main pathway of entry. Altogether, our data support the evidence of quasispecies fighting for host dominance by taking benefit from the cell machinery to restrict the productive infection of competitors in the viral ensemble. This finding may explain, at least in part, the extraordinary rapid worldwide turnover of VOCs that use the PM fusion pathway to enter into target cells over the original pandemic strain.
Implementing and Evaluating a Fellowship for Community-Based Physicians and Physician Assistants: Leadership, Practice Transformation, and Precepting
Authors: Casola Allison R. , Cunningham Amy , Crittendon Denine , Kelly Samantha , Sifri Randa , Arenson Christine
Published: May 2022

Introduction:

Formal training in practice transformation, leadership, clinical education, and/or the time to gain these skills are limited postresidency for primary care physicians and physician assistants. Therefore, we created a novel Primary Care Champions fellowship program that provides practical experiences in education, practice transformation, and leadership for primary care physicians and physician assistants in community practice. The purpose of this study is to describe the fellowship and evaluate feedback from the first cohort.

Methods:

In the Jefferson Primary Care Champions Fellowship, fellows are provided protected time from clinical obligations to engage in didactic, informal, and experiential learning. They meet monthly and participate in student precepting training and receive mentorship from senior clinician administrators, scientists, educators, and population health researchers to hone skills for leadership and practice transformation endeavors. Cohort one began in September 2018. All fellows were family physicians from community-based practices in Philadelphia, PA (N = 4) and selected in collaboration with their practice leadership. Mixed-methods postprogram evaluations included Organizational Readiness Assessment and qualitative feedback.

Results:

Fellows denoted individual time, small-group mentorship, protected project time, and open-robust discussions about primary care most useful. Three fellows reported that they plan to continue their practice-improvement projects postfellowship and one published her initial project findings and reflections.

Discussion:

Overall feedback from the first cohort was positive. Fellows greatly appreciated structured time to explore primary care interests, contemplated long-term career prospects, and considered leadership opportunities. Cohort two is currently underway and cohort three is in recruitment.
Protometabolism as out-of-equilibrium chemistry
Authors: Nader Serge , Sebastianelli Lorenzo , Mansy Sheref S.
Published: May 2022

It is common to compare life with machines. Both consume fuel and release waste to run. In biology, the engine that drives the living system is referred to as metabolism. However, attempts at deciphering the origins of metabolism do not focus on this energetic relationship that sustains life but rather concentrate on nonenzymatic reactions that produce all the intermediates of an extant metabolic pathway. Such an approach is akin to studying the molecules produced from the burning of coal instead of deciphering how the released energy drives the movement of pistons and ultimately the train when investigating the mechanisms behind locomotion. Theories that do explicitly invoke geological chemical gradients to drive metabolism most frequently feature hydrothermal vent conditions, but hydrothermal vents are not the only regions of the early Earth that could have provided the fuel necessary to sustain the Earth's first (proto)cells. Here, we give examples of prior reports on protometabolism and highlight how more recent investigations of out-of-equilibrium systems may point to alternative scenarios more consistent with the majority of prebiotic chemistry data accumulated thus far.

This article is part of the theme issue ‘Emergent phenomena in complex physical and socio-technical systems: from cells to societies’.
Strengthened second law for multi-dimensional systems coupled to multiple thermodynamic reservoirs
Authors: Wolpert David H.
Published: May 2022

The second law of thermodynamics can be formulated as a restriction on the evolution of the entropy of any system undergoing Markovian dynamics. Here I show that this form of the second law is strengthened for multi-dimensional, complex systems, coupled to multiple thermodynamic reservoirs, if we have a set of
a priori
constraints restricting how the dynamics of each coordinate can depend on the other coordinates. As an example, this strengthened second law (SSL) applies to complex systems composed of multiple physically separated, co-evolving subsystems, each identified as a coordinate of the overall system. In this example, the constraints concern how the dynamics of some subsystems are allowed to depend on the states of the other subsystems. Importantly, the SSL applies to such complex systems even if some of its subsystems can change state simultaneously, which is prohibited in a multipartite process. The SSL also strengthens previously derived bounds on how much work can be extracted from a system using feedback control, if the system is multi-dimensional. Importantly, the SSL does not require local detailed balance. So it potentially applies to complex systems ranging from interacting economic agents to co-evolving biological species.

This article is part of the theme issue ‘Emergent phenomena in complex physical and socio-technical systems: from cells to societies’.
Emergence as the conversion of information: a unifying theory
Authors: Varley Thomas F. , Hoel Erik
Published: May 2022

Is reduction always a good scientific strategy? The existence of the special sciences above physics suggests not. Previous research has shown that dimensionality reduction (macroscales) can increase the dependency between elements of a system (a phenomenon called ‘causal emergence’). Here, we provide an umbrella mathematical framework for emergence based on information conversion. We show evidence that coarse-graining can convert information from one ‘type’ to another. We demonstrate this using the well-understood mutual information measure applied to Boolean networks. Using partial information decomposition, the mutual information can be decomposed into redundant, unique and synergistic information atoms. Then by introducing a novel measure of the synergy bias of a given decomposition, we are able to show that the synergy component of a Boolean network’s mutual information can increase at macroscales. This can occur even when there is no difference in the total mutual information between a macroscale and its underlying microscale, proving information conversion. We relate this broad framework to previous work, compare it to other theories, and argue it complexifies any notion of universal reduction in the sciences, since such reduction would likely lead to a loss of synergistic information in scientific models.

This article is part of the theme issue ‘Emergent phenomena in complex physical and socio-technical systems: from cells to societies’.
Effect of delay on the emergent stability patterns in generalized Lotka–Volterra ecological dynamics
Authors: Saeedian Meghdad , Pigani Emanuele , Maritan Amos , Suweis Samir , Azaele Sandro
Published: May 2022

Understanding the conditions of feasibility and stability in ecological systems is a major challenge in theoretical ecology. The seminal work of May in 1972 and recent developments based on the theory of random matrices have shown the existence of emergent universal patterns of both stability and feasibility in ecological dynamics. However, only a few studies have investigated the role of delay coupled with population dynamics in the emergence of feasible and stable states. In this work, we study the effects of delay on generalized Loka–Volterra population dynamics of several interacting species in closed ecological environments. First, we investigate the relation between feasibility and stability of the modelled ecological community in the absence of delay and find a simple analytical relation when intra-species interactions are dominant. We then show how, by increasing the time delay, there is a transition in the stability phases of the population dynamics: from an equilibrium state to a stable non-point attractor phase. We calculate analytically the critical delay of that transition and show that it is in excellent agreement with numerical simulations. Finally, following a similar approach to characterizing stability in empirical studies, we investigate the coefficient of variation, which quantifies the magnitude of population fluctuations. We show that in the oscillatory regime induced by the delay, the variability at community level decreases for increasing diversity.

This article is part of the theme issue ‘Emergent phenomena in complex physical and socio-technical systems: from cells to societies’.
Emergence of functional information from multivariate correlations
Authors: Adami Christoph , C G Nitash
Published: May 2022

The information content of symbolic sequences (such as nucleic or amino acid sequences, but also neuronal firings or strings of letters) can be calculated from an ensemble of such sequences, but because information cannot be assigned to single sequences, we cannot correlate information to other observables attached to the sequence. Here we show that an informationscoreobtained from multivariate (multiple-variable) correlations within sequences of a ‘training’ ensemble can be used to predict observables of out-of-sample sequences with an accuracy that scales with the complexity of correlations, showing that functional information emerges from a hierarchy of multi-variable correlations.

This article is part of the theme issue ‘Emergent phenomena in complex physical and socio-technical systems: from cells to societies’.
Diversity of carbapenemase-producing Enterobacterales in England as revealed by whole-genome sequencing of isolates referred to a national reference laboratory over a 30-month period
Authors: Hopkins Katie L. , Ellaby Nicholas , Ellington Matthew J. , Doumith Michel , Mustafa Nazim , Meunier Danièle , Woodford Neil
Published: May 2022

Introduction. Increasing numbers of carbapenemase-producing

Enterobacterales

(CPE), which can be challenging to treat, have been referred to the national reference laboratory in England since the early 2000s.

Gap Statement/Aim. Previous studies on CPE in the UK have focussed on localized outbreaks. We applied whole-genome sequencing (WGS) to isolates referred to the national reference laboratory over 30 months to inform our understanding of CPE epidemiology in England.

Methodology. The first confirmed CPE from each new patient referred by an English diagnostic laboratory between 1 January 2014 and 30 June 2016 was sequenced on an Illumina HiSeq 2500. Multiple isolates from the same patient were included from either different species or the same species with different carbapenemase genes. The data were analysed using an in-house bioinformatics pipeline that determines species identification, multi-locus sequence typing (MLST) profile and antimicrobial resistance gene content.

Results. A total of 2658 non-duplicate CPE were sequenced amongst which three host organisms belonging to diverse sequence types (STs) predominated:

Klebsiella pneumoniae

(1380/2658, 51.9 %; 177 STs),

Escherichia coli

(723/2658, 27.2 %; 133 STs) and

Enterobacter cloacae

(294/2658, 11.1 %; 88 STs). Thirty different carbapenemase gene variants were identified, although bla
OXA-48-like (1122/2658, 42.2%), bla
NDM (692/2658, 26.0 %), bla
KPC (571/2658, 21.5 %), bla
VIM (100/2658, 3.8 %) and bla
IMP (33/2658, 1.2 %) predominated. ST/carbapenemase gene pairings represented widely distributed high-risk clones or clusters at a regional or hospital level.

Conclusion. CPE referred to the national reference laboratory are diverse, suggesting multiple introductions to England and a role for horizontal transfer of carbapenemase genes in English CPE epidemiology.
Factors Related to Stress in Children with Online Media Learning Methods during a Pandemic at Jaya Mulya 1 Elementary School, Karawang-Indonesia
Authors: Bayuningsih Ratih , Sidik Fajar
Published: May 2022

Stress on students is a condition that occurs when there is pressure at school that makes students feel burdened. This study aims to determine the factors related to stress in students who attend school with online media during the covid-19 pandemic at SDN Jayamulya 1 Kab. Karawang. This study uses a descriptive analytic design with a cross sectional approach with a population of 57 respondents and the sample used is 57 respondents. The results of this study there is a relationship between high achievement pressure factors and stress with a p-value of 0.022 < 0.05, a busy schedule factor with stress with a p-value of 0.012 < 0.05, academic achievement factors with stress with a p-value of 0.000 <0.05, physical demands factor with stress with p-value 0.036 < 0.05.
Allogeneic Hematopoietic Cell Transplants as Dynamical Systems: Effect of Early-Term Immune Suppression Intensity on Long-Term T Cell Recovery
Authors: Zelikson Viktoriya , Sabo Roy , Serrano Myrna , Aqeel Younus , Ward Savannah , Juhaishi Taha Al , Aziz May , Krieger Elizabeth , Simmons Gary , Roberts Catherine , Reed Jason , Buck Gregory , Toor Amir
Published: May 2022

Reduced intensity conditioning (RIC) is fraught with risk for disease relapse. This may be overcome by donor T cell alloreactivity. Reducing the duration of intense immune suppression in the early term following transplantation may create an immunologic environment favoring rapid T cell reconstitution to influence longer term transplant outcomes. Twenty-six patients were adaptively randomized based on donor-derived T cell recovery, between 2 different dosing schedules of mycophenolate mofetil (MMF): MMF for 30 days post-transplant, with filgrastim for cytokine support (MMF30 arm, 11 patients), or MMF for 15 days post-transplant, with sargramostim (MMF15 arm, 15 patients). All patients were treated with anti-thymocyte globulin at a dose of 1.7 mg/kg/day from day - 9 through day -7 and total body irradiation, 450 cGy given in 3 fractions. Patients were well matched between the study arms and underwent HLA matched related and unrelated donor hematopoietic cell transplantation (HCT). The MMF15 arm demonstrated superior T cell recovery in the first month. This difference persisted through the first year for total T cells, T cell subsets and NK cells. T cell repertoire tended to be more diverse in the MMF15 arm. The long term superior immune recovery in the MMF15 arm is consistent with a disproportionate impact of early interventions in HCT. Clinically, shorter course MMF post-transplant was not associated with increased risk of acute or chronic graft vs. host disease (GVHD), and relapse and there was a trend toward improved overall survival in the MMF15 arm. Reducing the duration of intense immunosuppression in the early term and the use of sargramostim following allogeneic HCT is feasible and leads to superior long-term T cell recovery. This regimen should be studied to improve immune recovery in large cohorts of patients undergoing HCT with RIC.
Estimation of the Ascertainment Bias in Covid Case Detection During the Omicron Wave
Authors: Elbanna Ahmed
Published: May 2022

Covid cases in the general population have been historically underreported due to a variety of reasons including limited access to PCR testing at the start of the pandemic, lack of nation-wide surveillance testing, and discouraged testing unless symptomatic. Concerns about underreporting have increased during the Omicron surge due to the expanded use of at-home rapid tests which are not required to be officially reported. For the state of Illinois, we have found that reported cases constituted only 50%-70% of the actual cases during the pre-Omicron waves (August 2020-December 2021). During the first Omicron (BA1) wave, this fraction dropped to 20-29% (i.e., only 1 in 4 to 1 in 5 cases are reported). During the ongoing second Omicron (BA2) surge, this fraction has further decreased to 12-18% (i.e., only 1 in 6 to 1 in 8 cases are reported). These estimates have important implications on understanding the extent of the Omicron surge at the state and national levels.
Factors influencing Blacks and Whites’ participation in Alzheimer’s disease biomarker research
Authors: Eliacin Johanne , Hathaway Elizabeth , Wang Sophia , O’Connor Caitlin , Saykin Andrew J. , Cameron Kenzie A.
Published: May 2022

INTRODUCTION

Alzheimer’s disease (AD) is a public health priority. AD biomarkers may vary based on race, but recruitment of diverse participants has been challenging.

METHODS

Three groups of Black and White participants with and without prior research advocacy or participation were interviewed individually or in focus groups to better understand perspectives related to AD biomarker research participation. Thematic analytic approach was used to analyze the data.

RESULTS

Identified barriers to AD biomarker research participation included hesitancy due to fear, distrust of research and researchers, lack of relevant knowledge, and lack of research test results disclosure. Drivers for engagement in biomarker research procedures included knowledge about research, AD, and related clinical procedures, perceived benefits of participation, and outreach from trusted sources.

DISCUSSION

Participants’ comments related to the need for diversity in research and desire for results disclosure suggest opportunities to engage Black individuals.
Trends in Diabetes Biomarkers and Treatment Statuses of Non-Institutionalized Canadians: Canadian Health Measures Survey 2007 to 2015
Authors: Chao Yi-Sheng
Published: May 2022

Background

Diabetes has been a major source of disease burden in Canada. Moreover, untreated diabetes can lead to complications and severe conditions. A few studies exist on the prevalence of diabetes and the adequacy of diabetes management for the Canadian population, and so this study aims to estimate the diabetes prevalence rates using biomarkers and the treatment statuses of non-institutionalized Canadian patients.

Methods

The Canadian Health Measures Survey (CHMS) cycles 1 to 4 were conducted between 2007 and 2015 as interviews with non-institutionalized Canadians. Four blood diabetic markers were measured: insulin, glycosylated hemoglobin percentages, random-spot glucose, and fasting glucose. Subjects with levels higher than normal ranges were considered to have pre-diabetes or diabetes. Treatment statuses were categorized into treated (using anti-diabetic agents or diagnosed with diabetes), probably treated (taking prescriptions or diagnosed with chronic conditions), potentially treated (taking any medications or diagnosed with chronic conditions), and untreated (not taking any medications and not diagnosed with chronic conditions). Weights were applied to generate nationally representative statistics.

Results

The blood insulin levels in cycle 4 were significantly higher than those in cycle 1 (ratio = 1.42, 95% CI = 1.04 to 1.79). The proportions of patients with pre-diabetes and diabetes were estimated differently at 0.75% using random-spot glucose and 42.17% using glycosylated hemoglobin percentages, respectively. The proportions of Canadians with uncontrolled pre-diabetes or diabetes varied from 0.59% using random-spot glucose levels to 4.63% using fasting glucose levels, respectively. Through cycles 1 to 4, the proportions of untreated Canadians with pre-diabetes or diabetes ranged from 3.86% to 3.73%. More than 93% of those with high fasting glucose levels were taking prescription medications or had been diagnosed with chronic conditions (probably treated). Less than 33% of those with high fasting glucose levels were diagnosed or actively being treated with anti-diabetic agents (treated).

Conclusion

Diabetes biomarkers might be useful for screening untreated and undertreated patients with pre-diabetes or diabetes. The treatment categories we used indicated different intensities of intervention that might be useful for determining levels of patient outreach and for planning targeted screening in Canada.