A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (for example, warmer ...environments
, younger populations
) have yet to be framed within a comprehensive analysis. We synthesized factors hypothesized to drive the pace and burden of this pandemic in SSA during the period from 25 February to 20 December 2020, encompassing demographic, comorbidity, climatic, healthcare capacity, intervention efforts and human mobility dimensions. Large diversity in the probable drivers indicates a need for caution in interpreting analyses that aggregate data across low- and middle-income settings. Our simulation shows that climatic variation between SSA population centers has little effect on early outbreak trajectories; however, heterogeneity in connectivity, although rarely considered, is likely an important contributor to variance in the pace of viral spread across SSA. Our synthesis points to the potential benefits of context-specific adaptation of surveillance systems during the ongoing pandemic. In particular, characterizing patterns of severity over age will be a priority in settings with high comorbidity burdens and poor access to care. Understanding the spatial extent of outbreaks warrants emphasis in settings where low connectivity could drive prolonged, asynchronous outbreaks resulting in extended stress to health systems.
•Sorting by total expected costs improved consumers’ choice of the lowest cost plan.•More vulnerable consumers experienced the largest relative improvements.•Providing additional education did not ...improve decisions further.•Results were robust to design manipulations where costs were uncertain.
We examine the effectiveness of alternate choice architectures for health plan choice in US marketplaces under the Affordable Care Act (ACA) using three experiments based on the Health Reform Monitoring Survey: two experiments tested how choice architectures used in presenting information on health plans influenced plan choices and how existing designs could be improved; the third experiment checked the robustness of the choice architecture effects to more naturalistic choice scenarios in which consumers select plans when future medical spending is uncertain. More vulnerable consumers (e.g., worse health, lower literacy) experienced the largest relative improvements when ACA marketplace plans were displayed and sorted by total expected costs for the year rather than premiums (Experiment 1). The benefits of sorting plans by total expected costs was not improved further by making the importance of total expected costs more salient or by providing just-in-time education about such costs (Experiment 2). However, just-in-time education increased the likelihood consumers did not choose a plan, suggesting they may be in the process of updating their plan selection strategy given the new information. Broadly, these results were consistent across alternative scenarios where total expected costs were subject to uncertainty and consistent with expected patterns of consumer behavior under risk aversion (Experiment 3). Thus, a policy-feasible mechanism—sorting health plan options by and highlighting total expected costs—may improve health plan choices, saving money for consumers and the government.
Macrocyclic peptides are sought-after molecular scaffolds for drug discovery, and new methods to access diverse libraries are of increasing interest. Here, we report the enzymatic synthesis of ...pyridine-based macrocyclic peptides (pyritides) from linear precursor peptides. Pyritides are a recently described class of ribosomally synthesized and post-translationally modified peptides (RiPPs) and are related to the long-known thiopeptide natural products. RiPP precursors typically contain an N-terminal leader region that is physically engaged by the biosynthetic proteins that catalyze modification of the C-terminal core region of the precursor peptide. We demonstrate that pyritide-forming enzymes recognize both the leader region and a C-terminal tripeptide motif, with each contributing to site-selective substrate modification. Substitutions in the core region were well-tolerated and facilitated the generation of a wide range of pyritide analogues, with variations in macrocycle sequence and size. A combination of the pyritide biosynthetic pathway with azole-forming enzymes was utilized to generate a thiazole-containing pyritide (historically known as a thiopeptide) with no similarity in sequence and macrocycle size to the naturally encoded pyritides. The broad substrate scope of the pyritide biosynthetic enzymes serves as a future platform for macrocyclic peptide lead discovery and optimization.
Six baleen whale species are found in the temperate western North Atlantic Ocean, with limited information existing on the distribution and movement patterns for most. There is mounting evidence of ...distributional shifts in many species, including marine mammals, likely because of climate‐driven changes in ocean temperature and circulation. Previous acoustic studies examined the occurrence of minke (Balaenoptera acutorostrata) and North Atlantic right whales (NARW; Eubalaena glacialis). This study assesses the acoustic presence of humpback (Megaptera novaeangliae), sei (B. borealis), fin (B. physalus), and blue whales (B. musculus) over a decade, based on daily detections of their vocalizations. Data collected from 2004 to 2014 on 281 bottom‐mounted recorders, totaling 35,033 days, were processed using automated detection software and screened for each species' presence. A published study on NARW acoustics revealed significant changes in occurrence patterns between the periods of 2004–2010 and 2011–2014; therefore, these same time periods were examined here. All four species were present from the Southeast United States to Greenland; humpback whales were also present in the Caribbean. All species occurred throughout all regions in the winter, suggesting that baleen whales are widely distributed during these months. Each of the species showed significant changes in acoustic occurrence after 2010. Similar to NARWs, sei whales had higher acoustic occurrence in mid‐Atlantic regions after 2010. Fin, blue, and sei whales were more frequently detected in the northern latitudes of the study area after 2010. Despite this general northward shift, all four species were detected less on the Scotian Shelf area after 2010, matching documented shifts in prey availability in this region. A decade of acoustic observations have shown important distributional changes over the range of baleen whales, mirroring known climatic shifts and identifying new habitats that will require further protection from anthropogenic threats like fixed fishing gear, shipping, and noise pollution.
Limited information exists on the distribution and movement patterns for most baleen whale species in the western North Atlantic Ocean. Previously, we conducted a broad‐scale passive acoustic monitoring study to analyze North Atlantic right whale seasonal distribution and shifts therein, based on identified changes in occurrence patterns starting in 2010. This study uses similar acoustic datasets and protocols to understand the seasonal distribution of humpback, sei, fin, and blue whales within the western North Atlantic, and to determine whether any of these species exhibited similar shifts in distribution patterns across time.
Open approaches for esophagectomy are often still useful; of these, left thoracoabdominal esophagectomy (TAE) is poorly understood and often criticized. Hence, we examined TAE’s worldwide ...utilization, survival, and present-day use and outcomes at our institution compared with contemporary national averages.
The Worldwide Esophageal Cancer Collaboration database includes 8854 patients who underwent esophagectomy for cancer between 2005 and 2014, a period when TAE was our center’s most common approach. Two propensity score–matched models were constructed: worldwide TAE vs worldwide non-TAE (751 matched pairs); and our high-volume center TAE vs worldwide non-TAE (273 matched pairs). All-cause mortality was compared between matched groups. Institutional TAE data from 2017 to 2021 were assessed for present-day use and outcomes.
Worldwide, propensity score–matched patients undergoing TAE had a median of 20 lymph nodes resected vs 17 after non-TAE (P < .0001). Five-year survival was 34% for worldwide TAE vs 42% for worldwide non-TAE groups (P = .04). Three-year matched survival was 52% for high-volume TAE compared with 54% for worldwide non-TAE groups (P = .1). From 2017 to 2021 at our institution, 90 (26%) of 346 esophagectomies were performed by TAE. Pneumonia developed in 5 patients (5.6%), with 88 patients (98%) alive at 30 days, comparable to contemporary averages of The Society of Thoracic Surgeons.
When it is performed as the primary approach in high volumes, TAE can have comparable outcomes to non-TAE with low morbidity. At present, we find that TAE is most useful in patients with truncal obesity, prior abdominal operations, and locally advanced cardia tumors with potential for variable extent of resection.
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The role of structurally dynamic genomic regions in speciation is poorly understood due to challenges inherent in diploid genome assembly. Here we reconstructed the evolutionary dynamics of ...structural variation in five cat species by phasing the genomes of three interspecies F1 hybrids to generate near-gapless single-haplotype assemblies. We discerned that cat genomes have a paucity of segmental duplications relative to great apes, explaining their remarkable karyotypic stability. X chromosomes were hotspots of structural variation, including enrichment with inversions in a large recombination desert with characteristics of a supergene. The X-linked macrosatellite DXZ4 evolves more rapidly than 99.5% of the genome clarifying its role in felid hybrid incompatibility. Resolved sensory gene repertoires revealed functional copy number changes associated with ecomorphological adaptations, sociality and domestication. This study highlights the value of gapless genomes to reveal structural mechanisms underpinning karyotypic evolution, reproductive isolation and ecological niche adaptation.
Video capsule endoscopy (VCE), approved by the U.S. Food and Drug Administration (FDA) in 2001, represented a disruptive technology that transformed evaluation of the small intestine. Adoption of ...this technology over time and current use within the U.S. clinical population has not been well described.
To assess the growth of capsule endoscopy within the U.S. Medicare provider population (absolute growth and on a population-adjusted basis), characterize the providers performing VCE, and describe potential regional differences in use. Medicare summary data from 2003 to 2019 were used to retrospectively analyze capsule endoscopy use in a multiple cross-sectional design. In addition, detailed provider summary files were used from 2012 to 2018 to characterize provider demographics.
VCE use grew rapidly from 2003 to 2008 followed by a plateau from 2008 to 2019. There was significant variation in use of VCE between states, with up to 10-fold variation between states (14.6 to 156.1 per 100,000 enrollees in 2018). During this time, the adjusted VCE use on a population-adjusted basis declined, reflecting saturation of growth.
Growth of VCE use over time follows an S-shaped diffusion of innovation curve demonstrating a successful diffusion of innovation within gastroenterology. The lack of additional growth since 2008 suggests that current levels of use are well matched to overall population need within the constraints of reimbursement. Future studies should examine whether this lack of growth has implications for access and healthcare inequities.
Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in ...genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in
TREX1, RNASEH2A, RNASEH2B, and
RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an
RNASEH2A or
RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous
TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in
TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in
RNASEH2A, RNASEH2B, and
RNASEH2C were missense. We identified an
RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with
TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to
RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with
TREX1, RNASEH2A, and
RNASEH2C mutations versus 8.0%
RNASEH2B mutation–positive patients were known to have died (
P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.
"Target trial emulation" has been proposed as an observational method to answer comparative effectiveness questions, but it has rarely been attempted concurrently with a randomized clinical trial ...(RCT).
We tested the hypothesis that blinded analysts applying target trial emulation to existing observational data could predict the results of an RCT.
PreVent (Preventing Hypoxemia with Manual Ventilation during Endotracheal Intubation) was a multicenter RCT examining the effects of positive-pressure ventilation during tracheal intubation on oxygen saturation and severe hypoxemia. Analysts unaware of PreVent's results used patient-level data from three previous trials evaluating airway management interventions to emulate PreVent's eligibility criteria, randomization procedure, and statistical analysis. After PreVent's release, results of this blinded observational analysis were compared with those of the RCT. Difference-in-differences estimates for comparison of treatment effects between the observational analysis and the PreVent trial are reported on the absolute scale.
Using observational data, we were able to emulate PreVent's randomization procedure to produce balanced groups for comparison. The lowest oxygen saturation during intubation was higher in the positive-pressure ventilation group than the no positive-pressure ventilation group in the observational analysis (
= 360; mean difference = 1.8%; 95% confidence interval CI = -1.0 to 4.6) and in the PreVent trial (
= 401; mean difference = 3.9%; 95% CI = 1.4 to 6.4), though the observational analysis could not exclude no difference. Difference-in-differences estimates comparing treatment effects showed reasonable agreement for lowest oxygen saturation between the observational analysis and the PreVent trial (mean difference = -2.1%; 95% CI = -5.9 to 1.7). Positive-pressure ventilation resulted in lower rates of severe hypoxemia in both the observational analysis (risk ratio = 0.60; 95% CI = 0.38 to 0.93) and in the PreVent trial (risk ratio = 0.48; 95% CI = 0.30 to 0.77). The absolute reduction in the incidence of severe hypoxemia with positive-pressure ventilation was similar in the observational analysis (9.4%) and the PreVent trial (12.0%), though the difference between these estimates had wide CIs (mean difference = 2.5%; 95% CI = -8.0 to 13.6%).
Applying target trial emulation methods to existing observational data for the evaluation of a novel intervention produced results similar to those of a randomized trial. These findings support the use of target trial emulation for comparative effectiveness research.
Thiazole-containing pyritides (thiopeptides) are ribosomally synthesized and post-translationally modified peptides (RiPPs) that have attracted interest owing to their potent biological activities ...and structural complexity. The class-defining feature of a thiopeptide is a six-membered, nitrogenous heterocycle formed by an enzymatic 4 + 2-cycloaddition. In rare cases, piperidine or dehydropiperidine (DHP) is present; however, the aromatized pyridine is considerably more common. Despite significant effort, the mechanism by which the central pyridine is formed remains poorly understood. Building on our recent observation of the Bycroft–Gowland intermediate (i.e., the direct product of the 4 + 2-cycloaddition), we interrogated thiopeptide pyridine synthases using a combination of targeted mutagenesis, kinetic assays, substrate analogs, enzyme–substrate cross-linking, and chemical rescue experiments. Collectively, our data delineate roles for several conserved residues in thiopeptide pyridine synthases. A critical tyrosine facilitates the final aromatization step of pyridine formation. This work provides a foundation for further exploration of the 4 + 2-cycloaddition reaction and future customization of pyridine-containing macrocyclic peptides.
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