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Functional characteristics of the jaw apparatus, for example bite force, in vertebrates is a combination of the skeleton and the musculature. In birds, bite force has been measured directly or calculated using various methods including summation of forces generated by the different elements of the jaw musculature. However, there have been no reports of the relationships between body size with the mass of the different muscle groups in a closely related group of birds. This study explored allometry in the different jaw muscle masses from parrot (Psittaciformes) species differing in body mass by 40-fold. It was hypothesised that the different muscle masses would exhibit isometry with body mass and skull size. Parrot heads were dissected and the masses of the individual muscle complexes were recorded. Data were subjected to phylogenetically-controlled regression analysis to document scaling effects with body mass and skull size. Most, but not all muscles, exhibited positive allometry with body mass but most were isometric with skull size. Consequently, as parrots get bigger, their skulls get proportionally longer, but that the muscles within the head isometrically scaled relative to the size of these proportionally larger skulls. The large muscles imply greater bite forces in parrots than have been reported to date, which seems to be associated with an increase in skull size to accommodate more muscles. It is unknown whether this pattern is applicable to other birds within specific orders or even across birds as a whole. There needs to be further investigation into the allometry of the morphological and functional properties of the avian jaw musculature.

Dinosaur embryos cause a lot of excitement in the scientific literature and are often widely reported because of the general public's interest in dinosaur biology. Well-preserved, articulated oviraptorosaur embryos in eggs are usually interpreted as representing a stage of development close to hatching because of their large size and good level of skeletal ossification. Based on this evidence, a recent report suggested that the position of the one embryo's head was reminiscent of an avian-like hatching position. Here we explore how the developmental stage of well-preserved oviraptorosaur embryos can be estimated, rather than assumed. This will help in our understanding of their developmental biology and its evolutionary consequences. Using quantitative methods and comparison with modern crocodilian embryos, we show that all articulated oviraptorosaur embryos are small relative to the egg and most likely at a stage of development equivalent to around 50%–60% of the developmental period, that is, not even close to hatching. This conclusion is supported by the fact that many elements of the crocodilian skeleton are well ossified many weeks before hatching and the position of oviraptorosaur embryos’ heads was also comparable to a crocodilian embryo many days before hatching. Misunderstandings about the stage of the developmental biology of these well-preserved oviraptorosaur embryos hampers our understanding of the true nature of their reproductive biology. We urge a more conservative approach to their interpretation. This is important, because misunderstandings in the minds of the public about dinosaur biology are hard to counter once poorly evidenced ideas have been reported around the world.

Interpretation of fossil material using comparative anatomy often relies on relationships predicted from data collected from extant species. Some years ago, it was suggested that femur length of birds could be predicted from egg mass but this relationship was counter-intuitive because egg mass is usually related to a measure of body size. The original analysis was also not phylogenetically controlled. This study used the same data to determine phylogenetically controlled relationships for body mass versus egg mass, and egg mass versus femur length. Further analysis showed that order was important in the prediction of egg mass from either body mass or femur length. For some orders, the single regression estimate through all data significantly over-, or under-estimated egg mass. This problem was more pronounced for femur length compared with body mass. Extrapolation of the relationship between femur length and egg mass for large extinct birds seemed to be provide useful data for the Gastornithidae but under-estimated egg mass for other large bird species of a variety of families. Use of equations derived from extant birds to gain insight into the reproductive biology of extinct species needs to be undertaken with great care.

BackgroundLarge reductions in the global malaria burden have been achieved in the last decades, but plateauing funding poses a challenge for progressing towards the ultimate goal of malaria eradication. We aimed to determine the optimal strategy to allocate global resources to achieve this goal.MethodsUsing previously published mathematical models ofPlasmodium falciparumandPlasmodium vivaxtransmission incorporating insecticide-treated nets (ITNs) as an illustrative intervention, we sought to identify the global funding allocation that maximized impact under defined objectives and across a range of global funding budgets.ResultsWe found that the optimal strategy for case reduction closely mirrored an allocation framework that prioritizes funding for high-transmission settings, resulting in total case reductions of 76% (optimal strategy) and 66% (prioritizing high-transmission settings) at intermediate budget levels. Allocation strategies that had the greatest impact on case reductions were associated with lesser near-term impacts on the global population at risk, highlighting a trade-off between reducing burden and “shrinking the map” through a focus on near-elimination settings. The optimal funding distribution prioritized high ITN coverage in high-transmission settings endemic forP. falciparumonly, while maintaining lower levels in low-transmission settings. However, at high budgets, 62% of funding was targeted to low-transmission settings co-endemic forP. falciparumandP. vivax.ConclusionsThese results support current global strategies to prioritize funding to high-burdenP. falciparum-endemic settings in sub-Saharan Africa to minimize clinical malaria burden and progress towards elimination but highlight competing goals of reducing the global population at risk and addressing the burden ofP. vivax.

Transmission-blocking interventions can play an important role in combating malaria worldwide. Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody (TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers. Here we predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions. We developed a pharmaco-epidemiological model, tailored to 2 settings of differing transmission intensity with already established insecticide-treated nets and seasonal malaria chemoprevention interventions. Community-wide annual administration (at 80% coverage) of TB31F over a 3-year period was predicted to reduce clinical incidence by 54% (381 cases averted per 1000 people per year) in a high-transmission seasonal setting, and 74% (157 cases averted per 1000 people per year) in a low-transmission seasonal setting. Targeting school-aged children gave the largest reduction in terms of cases averted per dose. An annual administration of the transmission-blocking monoclonal antibody TB31F may be an effective intervention against malaria in seasonal malaria settings.

Background & aimsFALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers.MethodsBlood-based composite fibrosis scores, blood-based biomarkers, and imaging biomarkers were evaluated for patients with available data from FALCON 1at baseline through week 24. SomaSignal tests assessed protein signatures of NASH steatosis, inflammation, ballooning, and fibrosis in blood. Linear mixed-effect models were fit for each biomarker. Correlations and concordance were assessed between blood-based biomarkers, imaging, and histological metrics.ResultsAt week 24, pegbelfermin significantly improved blood-based composite fibrosis scores (ELF, FIB-4, APRI), fibrogenesis biomarkers (PRO-C3 and PC3X), adiponectin, CK-18, hepatic fat fraction measured by MRI-proton density fat fraction, and all four SomaSignal NASH component tests. Correlation analyses between histological and non-invasive measures identified four main categories: steatosis/metabolism, tissue injury, fibrosis, and biopsy-based metrics. Concordant and discordant effects of pegbelfermin on the primary endpoint vs. biomarker responses were observed; the most clear and concordant effects were on measures of liver steatosis and metabolism. A significant association between hepatic fat measured histologically and by imaging was observed in pegbelfermin arms.ConclusionsPegbelfermin improved NASH-related biomarkers most consistently through improvement of liver steatosis, though biomarkers of tissue injury/inflammation and fibrosis were also improved. Concordance analysis shows that non-invasive assessments of NASH support and exceed the improvements detected by liver biopsy, suggesting that greater consideration should be given to the totality of available data when evaluating the efficacy of NASH therapeutics.Clinical trial numberPost hoc analysis of NCT03486899.Impact and implicationsFALCON 1 was a study of pegbelfermin vs. placebo in patients with non-alcoholic steatohepatitis (NASH) without cirrhosis; in this study, patients who responded to pegbelfermin treatment were identified through examination of liver fibrosis in tissue samples collected through biopsy. In the current analysis, non-invasive blood- and imaging-based measures of fibrosis, liver fat, and liver injury were used to determine pegbelfermin treatment response to see how they compared with the biopsy-based results. We found that many of the non-invasive tests, particularly those that measured liver fat, identified patients who responded to pegbelfermin treatment, consistent with the liver biopsy findings. These results suggest that there may be additional value in using data from non-invasive tests, along with liver biopsy, to evaluate how well patients with NASH respond to treatment.

Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis.This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model.Preclinical.This study included a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) model and 6-week-old, male C57BL/6J mice (N = 78).This study was performed using: 3T: gradient-echo two-point Dixon and spin-echo (SE) echo-planar imaging elastography (200 Hz) and 7T: SE two-point Dixon and SE elastography (200 Hz).MRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG-FGF21v dosing (baseline), and after PEG-FGF21v treatment (WK4/8). Regions of interest for MRI-HFF and MRE-SS were delineated by J.L. and H.T. (5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and HE staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured.Two-tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE-SS at WK8, posterior means, and 95% credible intervals were presented.CDAHFD significantly increased baseline MRI-HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE-SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG-FGF21v significantly decreased MRI-HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE-SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RMRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data.1 TECHNICAL EFFICACY STAGE: 2.

Background & aims Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. Here, we evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering siRNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis. Approach & results NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the USA. Patients with HCV-SVR (for ≥1 year) and advanced fibrosis received once-weekly intravenous infusions of placebo or BMS-986263 (45 mg or 90 mg) for 12 weeks. The primary endpoint was ≥1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment and 2/15 (13%; placebo), 3/18 (17%; 45 mg), and 6/28 (21%; 90 mg) had METAVIR improvements of ≥1 stage at Week 12. Five patients in the 90 mg arm had Ishak improvements by ≥2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment-related AEs were infusion-related reactions in the BMS-986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients. Conclusions In patients with HCV-SVR, BMS-986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS-986263 in patients with active fibrogenesis is warranted.

YouthMappers helps to map fundamental features of rural communities across the countryside of Sierra Leone as an innovative model for how to bring power to villages across West Africa. Charting location of buildings, tracing streets, and pinpointing where utility poles dot the landscape inform efforts to design and install mini-grids in places without power or with insufficient service. By understanding settlement patterns, road connectivity, and the layout of current low-voltage distribution networks, the team speeds up and scales up design for rural electrification, contributing directly to SDG 7 to bring affordable and clean energy to communities and to SDG 9 to build resilient infrastructure in ways that foster innovation for mapping and beyond.

Public health officials played a critical role in COVID-19 mitigation and response efforts. In Kansas, 51 local health department (LHD) administrators and/or local health officers left their positions due to the pandemic between 15 March 2020 and 31 August 2021. The purpose of this study was to identify factors that led to turnover of Kansas local public health officials during the COVID-19 pandemic. Those eligible to participate in this study included former LHD administrators and/or health officers who were employed at or contracted by a Kansas LHD on 15 March 2020 and resigned, retired, or were asked to resign prior to 31 August 2021. Researchers used a demographic survey, a focus group, and key informant interviews to collect data. Twelve former LHD leaders participated in this study. Four themes emerged from phenomenological analysis: politicization of public health; a perceived lack of support; stress and burnout; and the public health infrastructure not working. The findings of this study can guide the Kansas public health system to address the issues leading to turnover of leadership and prevent future turnover. Future research must explore strategies for mitigating leadership turnover and identify alternative public health structures that could be more effective.

Introduction and Problem StatementThe aging US population has led to the increased prevalence of neurodegenerative diseases and the critical need for specialists with advanced training in the management of these conditions. Focus on Common Movement Disorders (FOCMD), a 2-day educational course hosted by Vanderbilt University, was started 16 years ago to provide neurology residents with exposure to the diagnosis and treatment of movement disorders.ObjectivesThe aim of the course was to provide early-career neurology residents with relevant exposure to the field of movement disorders, through which we hope to increase medical knowledge of movement disorders and common Food and Drug Administration (FDA)-approved therapies and inspire residents to pursue fellowship training in the field.Methods and Curriculum DescriptionFOCMD consists of lectures and small-group workshops that provide an overview of common movement disorders and approved therapies. All North American neurology residency program directors are invited to nominate a first-year or second-year resident. Attendees are administered standardized multiple-choice precourse and postcourse examinations to assess foundational knowledge of common movement disorders and FDA-approved therapies and to measure acquisition of the course material. Past participants are regularly surveyed to gauge their impression of the course's effect on fellowship selection and their utilization of therapies common in the treatment of movement disorders.Results and Assessment DataSince 2008, FOCMD has trained 854 neurology residents from 113 programs. Between 2010 and 2020, 507 residents completed the precourse and postcourse examinations. There was an increase of 22.4 (95% CI 20.67–24.49;p< 0.001) percentage points between the precourse and postcourse examinations or an additional 3.8 questions were answered correctly. Follow-up surveys were sent to 414 past participants, and 116 were completed. Survey responses revealed that 84% of past attendees completed a fellowship, 44% of which were in the field of movement disorders. In addition, 82% of past participants reported that the course affected subspecialty selection and 63% reported treating patients with movement disorders in their current practice.Discussion and Lessons LearnedExperience with FOCMD has shown it to be successful in introducing neurology residents to the subspecialty early in their career and increasing medical knowledge on movement disorders. An educational program of this format may also positively influence fellowship selection.

Nonalcoholic steatohepatitis (NASH) is a major cause of liver‐related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver‐related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high‐risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0‐4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3‐4) versus early fibrosis (stages 0‐2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis‐stage classification models were explored using a machine learning–based approach to prioritize the biomarkers for further evaluation. A four‐protein model differentiated patients with stage 0‐1 versus stage 2‐4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12‐protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model’s performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74‐0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score–based models for all three cohorts. Conclusion: A SOMAscan proteomics‐based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD.

Nest construction by Common Redstarts Phoenicurus phoenicurus is affected by localized habitat.This study investigated whether variation in nest construction observed over a wide geographical regio...