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ObjectiveThe vast majority of the 300 000 pregnancy-related deaths every year occur in South Asia and sub-Saharan Africa. Increased access to quality antepartum and intrapartum care can reduce pregnancy-related morbidity and mortality worldwide. We used a population-based cross-sectional cohort design to: (1) examine the sociodemographic risk factors and structural barriers associated with pregnancy care-seeking and institutional delivery, and (2) investigate the influence of residential distance to the nearest primary health facility in a rural population in Mali.MethodsA baseline household survey of Malian women aged 15-49 years was conducted between December 2016 and January 2017, and those who delivereda baby in the 5 years preceding the survey were included. This study leverages the baseline survey data from a cluster-randomised controlled trial to conduct a secondary analysis. The outcomes were percentage of women who received any antenatal care (ANC) and institutional delivery; total number of ANC visits; four or more ANC visits; first ANC visit in the first trimester.ResultsOf the 8575 women in the study, two-thirds received any ANC in their last pregnancy, one in 10 had four or more ANC visits and among those that received any ANC, about one-quarter received it in the first trimester. For every kilometre increase in distance to the nearest facility, the likelihood of the outcomes reduced by 5 percentage points (0.95; 95% CI 0.91 to 0.98) for any ANC; 4 percentage points (0.96; 95% CI 0.94 to 0.98) for an additional ANC visit; 10 percentage points (0.90; 95% CI 0.86 to 0.95) for four or more ANC visits; 6 percentage points (0.94; 95% CI 0.94 to 0.98) for first ANC in the first trimester. In addition, there was a 35 percentage points (0.65; 95% CI 0.56 to 0.76) decrease in likelihood of institutional delivery if the residence was within 6.5 km to the nearest facility, beyond which there was no association with the place of delivery. We also found evidence of increase in likelihood of receiving any ANC care and its intensity increased with having some education or owning a business.ConclusionThe findings suggest that education, occupation and distance are important determinants of pregnancy and delivery care in a rural Malian context.Trial registration numberNCT02694055.

Abstract Mass extinctions are considered to be quintessential examples of Court Jester drivers of macroevolution, whereby abiotic pressures drive a suite of extinctions leading to huge ecosystem changes across geological timescales. Most research on mass extinctions ignores species interactions and community structure, limiting inference about which and why species go extinct, and how Red Queen processes that link speciation to extinction rates affect the subsequent recovery of biodiversity, structure and function. Here, we apply network reconstruction, secondary extinction modelling and community structure analysis to the Early Toarcian (Lower Jurassic; 183 Ma) Extinction Event and recovery. We find that primary extinctions targeted towards infaunal guilds, which caused secondary extinction cascades to higher trophic levels, reproduce the empirical post-extinction community most accurately. We find that the extinction event caused a switch from a diverse community with high levels of functional redundancy to a less diverse, more densely connected community of generalists. Recovery was characterised by a return to pre-extinction levels of some elements of community structure and function prior to the recovery of biodiversity. Full ecosystem recovery took ~7 million years at which point we see evidence of dramatically increased vertical structure linked to the Mesozoic Marine Revolution and modern marine ecosystem structure.

Abstract ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure’s impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.

To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew (i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.

IntroductionThough community health workers (CHWs) have improved access to antenatal care (ANC) and institutional delivery in different settings, it is unclear what package and delivery strategy maximises impact.MethodsThis study reports a secondary aim of the Proactive Community Case Management cluster randomised trial, conducted between December 2016 and April 2020 in Mali. It evaluated whether proactive home visits can improve ANC access at a population level compared with passive site-based care. 137 unique village clusters, covering the entire study area, were stratified by health catchment area and distance to the nearest primary health centre. Within each stratum, clusters were randomly assigned to intervention or control arm. CHWs in intervention clusters proactively visited all homes to provide care. In the control clusters, CHWs provided the same services at their fixed community health post to care-seeking patients. Pregnant women 15-49 years old were enrolled in a series of community-based and facility-based visits. We analysed individual-level annual survey data from baseline and 24-month and 36-month follow-up for the secondary outcomes of ANC and institutional delivery, complemented with CHW monitoring data during the trial period. We compared outcomes between: (1) the intervention and control arms, and (2) the intervention period and baseline.ResultsWith 2576 and 2536 pregnancies from 66 and 65 clusters in the intervention and control arms, respectively, the estimated risk ratios for receiving any ANC was 1.05 (95% CI 1.02 to 1.07), four or more ANC visits was 1.25 (95% CI 1.08 to 1.43) and ANC initiated in the first trimester was 1.11 (95% CI 1.02 to 1.19), relative to the controls; no differences in institutional delivery were found. However, both arms achieved large improvements in institutional delivery, compared with baseline. Monitoring data show that 19% and 2% of registered pregnancies received at least eight ANC contacts in the intervention and control arms, respectively. Six clusters, three from each arm had to be dropped in the last 2 years of the trial.ConclusionsProactive home visits increased ANC and the number of antenatal contacts at the clinic and community levels. ANC and institutional delivery can be increased when provided without fees from professional CHWs in upgraded primary care clinics.Trial registration numberNCT02694055.

Abstract Background Studies on haemosporidian diversity, including origin of human malaria parasites, malaria's zoonotic dynamic, and regional biodiversity patterns, have used target gene approaches. However, current methods have a trade-off between scalability and data quality. Here, a long-read Next-Generation Sequencing protocol using PacBio HiFi is presented. The data processing is supported by a pipeline that uses machine-learning for analysing the reads. Methods A set of primers was designed to target approximately 6 kb, almost the entire length of the haemosporidian mitochondrial genome. Amplicons from different samples were multiplexed in an SMRTbell® library preparation. A pipeline (HmtG-PacBio Pipeline) to process the reads is also provided; it integrates multiple sequence alignments, a machine-learning algorithm that uses modified variational autoencoders, and a clustering method to identify the mitochondrial haplotypes/species in a sample. Although 192 specimens could be studied simultaneously, a pilot experiment with 15 specimens is presented, including in silico experiments where multiple data combinations were tested. Results The primers amplified various haemosporidian parasite genomes and yielded high-quality mt genome sequences. This new protocol allowed the detection and characterization of mixed infections and co-infections in the samples. The machine-learning approach converged into reproducible haplotypes with a low error rate, averaging 0.2% per read (minimum of 0.03% and maximum of 0.46%). The minimum recommended coverage per haplotype is 30X based on the detected error rates. The pipeline facilitates inspecting the data, including a local blast against a file of provided mitochondrial sequences that the researcher can customize. Conclusions This is not a diagnostic approach but a high-throughput method to study haemosporidian sequence assemblages and perform genotyping by targeting the mitochondrial genome. Accordingly, the methodology allowed for examining specimens with multiple infections and co-infections of different haemosporidian parasites. The pipeline enables data quality assessment and comparison of the haplotypes obtained to those from previous studies. Although a single locus approach, whole mitochondrial data provide high-quality information to characterize species pools of haemosporidian parasites.

Objective: To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis. Design: Observational study. Subjects/Patients: 70 people with multiple sclerosis. Methods: Perceived and physiological strain of societal participation (10 participation-at-location and 9 transport domains) were measured in real time using the Whereabouts smartphone app and Fitbit over 7 consecutive days. Longitudinal relationships between perceived (1 not strenuous to 10 most strenuous) and physiological strains (heart rate reserve) were examined using mixed-model analyses. Type of event (participation-at-location or transport) was added as covariate, with further adjustments for fatigue and walking ability. Results: Median perceived strain, summarized for all societal participation domains, varied between 3 and 6 (range: 1–10), whereas physiological strain varied between 18.5% and 33.2% heart rate reserve. Perceived strain (outcome) and physiological strain were not associated (β -0.001, 95%CI -0.008; 0.005, with a 7-day longitudinal correlation coefficient of -0.001). Transport domains were perceived as less strenuous (β -0.80, 95%CI -0.92; -0.68). Higher fatigue levels resulted in higher perceived strain (all societal participation domains) (β 0.05, 95%CI 0.02; 0.08). Conclusion: Societal participation resulted in low-to-moderate perceived and physiological strain. Perceived and physiological strain of societal participation were unrelated and should be considered different constructs in multiple sclerosis.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Abstract Background Chronological and biological age correlate with DNA methylation levels at specific sites in the genome. Linear combinations of multiple methylation sites, termed epigenetic clocks, can inform us the chronological age and predict multiple health-related outcomes. However, why some sites correlating with lifespan, healthspan, or specific medical conditions remain poorly understood. Kidney fibrosis is the common pathway for chronic kidney disease, which affects 10% of European and US populations. Results Here we identify epigenetic clocks and methylation sites that correlate with kidney function. Moreover, we identify methylation sites that have a unique methylation signature in the kidney. Methylation levels in majority of these sites correlate with kidney state and function. When kidney function deteriorates, all of these sites regress toward the common methylation pattern observed in other tissues. Interestingly, while the majority of sites are less methylated in the kidney and become more methylated with loss of function, a fraction of the sites are highly methylated in the kidney and become less methylated when kidney function declines. These methylation sites are enriched for specific transcription-factor binding sites. In a large subset of sites, changes in methylation patterns are accompanied by changes in gene expression in kidneys of chronic kidney disease patients. Conclusions These results support the information theory of aging, and the hypothesis that the unique tissue identity, as captured by methylation patterns, is lost as tissue function declines. However, this information loss is not random, but guided toward a baseline that is dependent on the genomic loci. Significance statement DNA methylation at specific sites accurately reflects chronological and biological age. We identify sites that have a unique methylation pattern in the kidney. Methylation levels in the majority of these sites correlate with kidney state and function. Moreover, when kidney function deteriorates, all of these sites regress toward the common methylation pattern observed in other tissues. Thus, the unique methylation signature of the kidney is degraded, and epigenetic information is lost, when kidney disease progresses. These methylation sites are enriched for specific and methylation-sensitive transcription-factor binding sites, and associated genes show disease-dependent changes in expression. These results support the information theory of aging, and the hypothesis that the unique tissue identity, as captured by methylation patterns, is lost as tissue function declines.

Endosymbiosis drives evolutionary innovation and underpins the function of diverse ecosystems. The mechanistic origins of symbioses, however, remain unclear, in part because early evolutionary events are obscured by subsequent evolution and genetic drift. This Essay highlights how experimental studies of facultative, host-switched, and synthetic symbioses are revealing the important role of fitness trade-offs between within-host and free-living niches during the early-stage evolution of new symbiotic associations. The mutational targets underpinning such trade-offs are commonly regulatory genes, such that single mutations have major phenotypic effects on multiple traits, thus enabling and reinforcing the transition to a symbiotic lifestyle.

Objective The vast majority of the 300 000 pregnancy-related deaths every year occur in South Asia and sub-Saharan Africa. Increased access to quality antepartum and intrapartum care can reduce pregnancy-related morbidity and mortality worldwide. We used a population-based cross-sectional cohort design to: (1) examine the sociodemographic risk factors and structural barriers associated with pregnancy care-seeking and institutional delivery, and (2) investigate the influence of residential distance to the nearest primary health facility in a rural population in Mali.Methods A baseline household survey of Malian women aged 15–49 years was conducted between December 2016 and January 2017, and those who delivereda baby in the 5 years preceding the survey were included. This study leverages the baseline survey data from a cluster-randomised controlled trial to conduct a secondary analysis. The outcomes were percentage of women who received any antenatal care (ANC) and institutional delivery; total number of ANC visits; four or more ANC visits; first ANC visit in the first trimester.Results Of the 8575 women in the study, two-thirds received any ANC in their last pregnancy, one in 10 had four or more ANC visits and among those that received any ANC, about one-quarter received it in the first trimester. For every kilometre increase in distance to the nearest facility, the likelihood of the outcomes reduced by 5 percentage points (0.95; 95% CI 0.91 to 0.98) for any ANC; 4 percentage points (0.96; 95% CI 0.94 to 0.98) for an additional ANC visit; 10 percentage points (0.90; 95% CI 0.86 to 0.95) for four or more ANC visits; 6 percentage points (0.94; 95% CI 0.94 to 0.98) for first ANC in the first trimester. In addition, there was a 35 percentage points (0.65; 95% CI 0.56 to 0.76) decrease in likelihood of institutional delivery if the residence was within 6.5 km to the nearest facility, beyond which there was no association with the place of delivery. We also found evidence of increase in likelihood of receiving any ANC care and its intensity increased with having some education or owning a business.Conclusion The findings suggest that education, occupation and distance are important determinants of pregnancy and delivery care in a rural Malian context.Trial registration number NCT02694055.

BackgroundPersistent challenges in meeting reproductive health and family planning goals underscore the value in determining what factors can be leveraged to facilitate modern contraceptive use, especially in poor access settings. In Mali, where only 15% of reproductive-aged women use modern contraception, understanding how women's realities and health system design influence contraceptive use helps to inform strategies to achieve the nation's target of 30% by 2023.MethodsUsing household survey data from the baseline round of a cluster-randomized trial, including precise geolocation data from all households and public sector primary health facilities, we used a multilevel model to assess influences at the individual, household, community, and health system levels on women's modern contraceptive use. In a three-level, mixed-effects logistic regression, we included measures of women's decision-making and mobility, as well as socio-economic sources of empowerment (education, paid labor), intrahousehold influences in the form of a co-residing user, and structural factors related to the health system, including distance to facility.ResultsLess than 5% of the 14,032 women of reproductive age in our study used a modern method of contraception at the time of the survey. Women who played any role in decision-making, who had any formal education and participated in any paid labor, were more likely to use modern contraception. Women had three times the odds of using modern contraception if they lived in a household with another woman, typically a co-wife, who also used a modern method. Compared to women closest to a primary health center, those who lived between 2 and 5 km were half as likely to use modern contraception, and those between 5 and 10 were a third as likely.ConclusionsDespite chronically poor service availability across our entire study area, some women-even pairings of women in single households-transcended barriers to use modern contraception. When planning and implementing strategies to expand access to contraception, policymakers and practitioners should consider women's empowerment, social networks, and health system design. Accessible and effective health systems should reconsider the conventional approach to community-based service delivery, including distance as a barrier only beyond 5 km.

BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Abstract All animals and plants respond to changes in the environment during their life cycle. This flexibility is known as phenotypic plasticity and allows organisms to cope with variable environments. A common source of environmental variation is predation risk, which describes the likelihood of being attacked and killed by a predator. Some species can respond to the level of predation risk by producing morphological defences against predation. A classic example is the production of so‐called ‘neckteeth’ in the water flea, Daphnia pulex, which defend against predation from Chaoborus midge larvae. Previous studies of this defence have focussed on changes in pedestal size and the number of spikes along a gradient of predation risk. Although these studies have provided a model for continuous phenotypic plasticity, they do not capture the whole‐organism shape response to predation risk. In contrast, studies in fish and amphibians focus on shape as a complex, multi‐faceted trait made up of different variables. In this study, we analyse how multiple aspects of shape change in D. pulex along a gradient of predation risk from Chaoborus flavicans. These changes are dominated by the neckteeth defence, but there are also changes in the size and shape of the head and the body. We detected change in specific modules of the body plan and a level of integration among modules. These results are indicative of a complex, multi‐faceted response to predation and provide insight into how predation risk drives variation in shape and size at the level of the whole organism.

Abstract Harnessing science‐based policy is key to addressing global challenges like the biodiversity and climate crises. Open research principles underpin effective science‐based policy, but the uptake of these principles is likely constrained by the politicisation, commoditisation and conflicting motives of stakeholders in the research landscape. Here, using the mission and vision statements from 129 stakeholders from across the research landscape, we explore alignment in open research principles between stakeholders. We find poor alignment between stakeholders, largely focussed around journals, societies and funders, all of which have low open research language‐use. We argue that this poor alignment stifles knowledge flow within the research landscape, ultimately limiting the mobilisation of impactful science‐based policy. We offer recommendations on how the research landscape could embrace open research principles to accelerate societies' ability to solve global challenges.

Objective: To examine the energy demand of walking relative to aerobic capacity in people with multiple sclerosis. Design: Cross-sectional cohort study. Patients: A total of 45 people with multiple sclerosis (32 females), median disease duration 15 years (interquartile range (IQR) 9; 20), median Expanded Disability Status Scale 4 (min–max range: 2.0; 6.0). Methods: Aerobic capacity, derived from a cardiopulmonary exercise test and gas exchange measurements, assessed during a 6-min overground walk test at comfortable speed, were analysed. The relative aerobic load of walking was determined as the energy demand of walking relative to oxygen uptake at peak and at the first ventilatory threshold. Healthy reference data were used for clinical inference. Results: People with multiple sclerosis walk at a mean relative aerobic load of 60.0% (standard deviation 12.8%) relative to peak aerobic capacity, and 89.1% (standard deviation 19.9%) relative to the first ventilatory threshold. Fourteen participants walked above the first ventilatory threshold (31%). Peak aerobic capacity was reduced in 45% of participants, and energy demands were increased in 52% of participants. Conclusion: People with multiple sclerosis walk at a relative aerobic load close to their first ventilatory threshold. A high relative aerobic load can guide clinicians to improve aerobic capacity or reduce the energy demands of walking.

Tristetraprolin (TTP) is an RNA binding protein that destabilizes mRNAs of factors involved in proliferation, invasiveness, and inflammation. Disruption of the gene that codes for TTP (Zfp36) led to severe arthritis, autoimmunity, cachexia and dermatitis in mice. It has been shown that these phenotypes were mostly due to excessive TNFα levels in the affected tissues. We have previously reported that TTP expression is required for lactation maintenance. Our results indicated that conditional MG TTP-KO female mice displayed early involution due to the untimely induction of pro-inflammatory pathways led mostly by TNFα overexpression. Here we show that reducing TTP levels not only affects the fully differentiated mammary gland, but also harms morphogenesis of this tissue by impairing the progenitor cell population. We found that Zfp36 expression is linked to mammary stemness in human and mice. In addition, diminishing TTP expression and activity induced apoptosis of stem-like mouse mammary cells, reduced its ability to form mammospheres in culture and to develop into complete glands when implanted into cleared mammary fat pads in vivo. Our results show that survival of the stem-like cells is compromised by increased levels of inflammatory cytokines and stimulation of signaling cascades involving NFκB, STAT3 and MAPK-p38 activation. Moreover, TNFα overexpression and the consequent p38 phosphorylation would be the leading cause of progenitor cell death upon TTP expression restriction. Taken together, our results reveal the relevance of TTP for the maintenance of the mammary progenitor cell compartment by maintaining local TNFα levels at bay.

Abstract Extreme swing of phosphor from severe hyperphosphatemia to severe hypophosphatemia in a patient with blast crisis of myeloid origin was the result of imbalance between massive apoptosis of leukemic cells in the context of spontaneous tumor lysis syndrome and massive production of leukemic cells with only 1% of blast in peripheral blood. The mutated p53 protein suggested acting as oncogene in the presented case and possibly affecting phosphor status.

Abstract Introduction In addition to significant morbidity and mortality, the coronavirus disease (COVID-19) has strained health care systems globally. This study investigated the cost-effectiveness of remdesivir + standard of care (SOC) for hospitalized COVID-19 patients in the USA. Methods This cost-effectiveness analysis considered direct and indirect costs of remdesivir + SOC versus SOC alone among hospitalized COVID-19 patients in the US. Patients entered the model stratified according to their baseline ordinal score. At day 15, patients could transition to another health state, and on day 29, they were assumed to have either died or been discharged. Patients were then followed over a 1-year time horizon, where they could transition to death or be rehospitalized. Results Treatment with remdesivir + SOC avoided, per patient, a total of 4 hospitalization days: two general ward days and a day for both the intensive care unit and the intensive care unit plus invasive mechanical ventilation compared to SOC alone. Treatment with remdesivir + SOC presented net cost savings due to lower hospitalization and lost productivity costs compared to SOC alone. In increased and decreased hospital capacity scenarios, remdesivir + SOC resulted in more beds and ventilators being available versus SOC alone. Conclusions Remdesivir + SOC alone represents a cost-effective treatment for hospitalized patients with COVID-19. This analysis can aid in future decisions on the allocation of healthcare resources.

This article describes the author's journey into the work of Patricia Carini and the descriptive processes developed at Prospect School and Center. The author begins with her first experiences learning to observe and describe children using Descriptive Review as a new teacher and graduate teacher education student. She goes on to discuss how this work and her experience as a Prospect Archives Practitioner Fellow followed her into her teaching practice with children and later into her work as a teacher educator. She examines both the personal and political implications this way of looking holds, and how it can be used as a tool for striving toward equity in schools.

Background: The majority of children with cerebral palsy (CP) experience challenges in functional communication from a young age. A pivotal aspect of functional communication is language comprehension. A variety of classification systems and questionnaires are available to classify and describe functional communication skills in children with CP. A better understanding of the convergent validity of (subsections of) these tools, as well as their relationship with spoken language comprehension, will be valuable in both clinical practice and research. Aims: To investigate the convergent validity of (subsections of) functional communication tools and the relationship with spoken language comprehension in children with CP. Methods & Procedures: Cross-sectional data on 138 children were subdivided into three developmental stages based on (Dutch) educational phases: ages 18 months-3;11y (n = 59), 4;0-5;11 years (n = 37) and 6;0-8;11 years (n = 42). The following functional communication tools were used to classify and describe functional communication: Communication Function Classification System (CFCS), subscales of the Caregivers Priorities and Child Health Index of Life with Disabilities--Dutch Version (CPCHILD-DV) and the Focus on Communication Under Six-34 (FOCUS-34) questionnaire. Spoken language comprehension was assessed with the Computer-Based instrument for Low motor Language Testing (C-BiLLT). Correlations between the functional communication tools, and with the C-BiLLT, were calculated using Pearson's and Spearman's correlation coefficients. It was hypothesized a priori that correlations of at least 0.60 suggest good convergent validity. Outcomes & Results: At all developmental stages, a significant ordered decreasing tendency of communication outcomes was found across CFCS levels; lower CFCS levels were associated with lower scores on the CPCHILD-DV and FOCUS-34, and with a lower level of spoken language comprehension (C-BiLLT). Correlation coefficients of the functional communication tools exceeded 0.60 at all developmental stages. Correlations between C-BiLLT raw scores and the functional communication tools varied between 0.351 and 0.591 at developmental stage 18 months-3;11 years, between 0.781 and 0.897 at developmental stage 4;0-5;11 years, and between 0.635 and 0.659 at developmental stage 6;0-8;11 years. Conclusions & Implications: The functional communication tools assessed in this study showed convergent validity at all developmental stages. The CFCS, currently most widely used in paediatric rehabilitation, is adequate in the classification of functional communication. However, for more detailed clinical goal setting and evaluation of change in functional communication, the additional use of FOCUS-34 or CPCHILD-DV is recommended.

Intermittent claudication (IC) from peripheral arterial disease is typically managed with pharmacologic interventions and lifestyle changes. However, despite societal guidelines, initial endovascular interventions are being used more frequently with an increased incidence of complications, resulting in rapid disease progression to critical and acute limb-threatening ischemia (ALI). The present report describes the case of a patient who developed ALI after treatment of IC at another facility, with malpositioned bilateral common iliac stents, continuous stent extension into the popliteal artery, and acute occlusion of the entirety of the right lower extremity vasculature. This case illustrates how extensive endovascular intervention for IC can result in ALI requiring urgent revascularization.

ObjectiveDuring the COVID-19 pandemic, central venous access line teams were implemented at many hospitals throughout the world to provide access for critically ill patients. The objective of this study was to describe the structure, practice patterns, and outcomes of these vascular access teams during the COVID-19 pandemic.MethodsWe conducted a cross-sectional, self-reported study of central venous access line teams in hospitals afflicted with the COVID-19 pandemic. To participate in the study, hospitals were required to meet one of the following criteria: development of a formal plan for a central venous access line team during the pandemic; implementation of a central venous access line team during the pandemic; placement of central venous access by a designated practice group during the pandemic as part of routine clinical practice; or management of an iatrogenic complication related to central venous access in a patient with COVID-19.ResultsParticipants from 60 hospitals in 13 countries contributed data to the study. Central venous line teams were most commonly composed of vascular surgery and general surgery attending physicians and trainees. Twenty sites had 2657 lines placed by their central venous access line team or designated practice group. During that time, there were 11 (0.4%) iatrogenic complications associated with central venous access procedures performed by the line team or group at those 20 sites. Triple lumen catheters, Cordis (Santa Clara, Calif) catheters, and nontunneled hemodialysis catheters were the most common types of central venous lines placed by the teams. Eight (14%) sites reported experience in placing central venous lines in prone, ventilated patients with COVID-19. A dedicated line cart was used by 35 (59%) of the hospitals. Less than 50% (24 [41%]) of the participating sites reported managing thrombosed central lines in COVID-19 patients. Twenty-three of the sites managed 48 iatrogenic complications in patients with COVID-19 (including complications caused by providers outside of the line team or designated practice group).ConclusionsImplementation of a dedicated central venous access line team during a pandemic or other health care crisis is a way by which physicians trained in central venous access can contribute their expertise to a stressed health care system. A line team composed of physicians with vascular skill sets provides relief to resource-constrained intensive care unit, ward, and emergency medicine teams with a low rate of iatrogenic complications relative to historical reports. We recommend that a plan for central venous access line team implementation be in place for future health care crises.

Human adaptation depends on the integration of slow life history, complex production skills, and extensive sociality. Refining and testing models of the evolution of human life history and cultural learning benefit from increasingly accurate measurement of knowledge, skills, and rates of production with age. We pursue this goal by inferring hunters' increases and declines of skill from approximately 23,000 hunting records generated by more than 1800 individuals at 40 locations. The data reveal an average age of peak productivity between 30 and 35 years of age, although high skill is maintained throughout much of adulthood. In addition, there is substantial variation both among individuals and sites. Within study sites, variation among individuals depends more on heterogeneity in rates of decline than in rates of increase. This analysis sharpens questions about the coevolution of human life history and cultural adaptation.

Study designRetrospective case series.ObjectivesBoth the rate and complexity of spine surgeries in elderly patients has increased. This study reports the outcomes of multilevel spine fusion in elderly patients and provides evidence on the appropriateness of complex surgery in elderly patients.MethodsWe identified 101 patients older than70 years who had ≥5 levels of fusion. Demographic, medical, and surgical data, and change between preoperative and >500 days postoperative health survey scores were collected. Health surveys were visual analogue scale (VAS), EuroQoL 5 Dimensions (EQ-5D), Oswestry Disability Index (ODI), Scoliosis Research Society questionnaire (SRS-30), and Short Form health survey (SF-12) (physical composite score [PCS] and mental composite score [MCS]). Minimal clinically important differences (MCIDs) were defined for each survey.ResultsComplications included dural tears (19%), intensive care unit admission (48%), revision surgery within 2 to 5 years (24%), and death within 2 to 5 years (16%). The percentage of patients who reported an improvement in health-related quality of life (HRQOL) of at least an MCID was: VAS Back 69%; EQ-5D 41%; ODI 58%; SRS-30 45%; SF-12 PCS 44%; and SF-12 MCS 48%. Improvement after a primary surgery, as compared with a revision, was on average 13 points higher in ODI (P = .007). Patients who developed a surgical complication averaged an improvement 11 points lower on ODI (P = .042). Patients were more likely to find improvement in their health if they had a lower American Society of Anesthesiologists or Charlson Comorbidity Index score or a higher metabolic equivalent score.ConclusionsIn multilevel surgery in patients older than 70 years, complications are common, and on average 77% of patients attain some improvement, with 51% reaching an MCID. Physiological status is a stronger predictor of outcomes than chronological age.

Study Design:Cost analysis of a retrospectively identified cohort of patients who had undergone primary single-level lumbar fusion at a single institution's orthopedic or neurosurgery department. Objective:The purpose of this article is to analyze the determinants of direct costs for single-level lumbar fusions and identify potential areas for cost reduction. Methods:Adult patients who underwent primary single-level lumbar fusion from fiscal years 2008 to 2012 were identified via administrative and departmental databases and were eligible for inclusion. Patients were excluded if they underwent multiple surgeries, had previous surgery at the same anatomic region, underwent corpectomy, kyphectomy, disc replacement, surgery for tumor or infection, or had incomplete cost data. Demographic data, surgical data, and direct cost data in the categories of supplies, services, room and care, and pharmacy, was collected for each patient. Results:The cohort included 532 patients. Direct costs ranged from $8286 to $73 727 (median = $21 781; mean = $22 890 ± $6323). Surgical approach was an important determinant of cost. The mean direct cost was highest for the circumferential approach and lowest for posterior instrumented spinal fusions without an interbody cage. The difference in mean direct cost between transforaminal lumbar interbody fusions, anterior lumbar interbody fusions, and lateral transpsoas fusions was not statistically significant. Surgical supplies accounted for 44% of direct costs. Spinal implants were the primary component of supply costs (84.9%). Services accounted for 38% of direct costs and were highly dependent on operative time. Comorbidities were an important contributor to variance in the cost of care as evidenced by high variance in pharmacy costs and length of stay related to their management. Conclusion:The costs of spinal surgeries are highly variable. Important cost drivers in our analysis included surgical approach, implants, operating room time, and length of hospital stay. Areas of high cost and high variance offer potential targets for cost savings and quality improvements.

Background The diagnosis of peritonitis among peritoneal dialysis (PD) patients is based on clinical presentation, dialysis effluent white blood cell (WBC) count, and dialysis effluent culture. Peritoneal fluid WBC count is very important in the initial diagnosis of peritonitis. The purpose of this work was to determine the optimal number of peritoneal WBCs with different clinical presentations at admission to define PD-related peritonitis. Methods Medical records of chronic PD patients who underwent work-up for suspected peritonitis between 2008 and 2019 were reviewed retrospectively. Results of all peritoneal WBC count tests during this period were collected. Clinical manifestations and follow-up analysis of each peritoneal WBC count were performed. Results The peritoneal WBC count cutoff of 100/μL recommended by International Society for Peritoneal Dialysis provided specificity of only 35%. Increasing peritoneal WBC count cutoff to 150, 200, and 250/μL provided sensitivity around 98% and gradually increasing specificity. The chi-square automatic interaction detector model of statistical analysis determined that peritoneal WBC count below 230/μL combined with absence of inflammatory markers (fever, increased C-reactive protein) ruled out peritonitis with 99.8% sensitivity. Peritoneal fluid WBC count cutoff of 230/μL provided specificity of 89% and good positive and negative likelihood scores of 8.3 and 0.03, respectively. Peritoneal fluid polymorphonuclear count has lower discriminating ability for peritonitis compared to peritoneal fluid WBC count. Conclusion Increasing peritoneal fluid WBC count cutoff to 230/μL in suspected PD-related peritonitis could improve specificity without compromising the sensitivity of the test.

Abstract Background This study reports the outcomes of Communities for Healthy Living (CHL), a cluster randomized obesity prevention trial implemented in partnership with Head Start, a federally-funded preschool program for low-income families. Methods Using a stepped wedge design, Head Start programs (n = 16; Boston, MA, USA) were randomly assigned to one of three intervention start times. CHL involved a media campaign and enhanced nutrition support. Parents were invited to join Parents Connect for Healthy Living (PConnect), a 10-week wellness program. At the beginning and end of each school year (2017-2019), data were collected on the primary outcome of child Body Mass Index z-score (BMIz) and modified BMIz, and secondary outcomes of child weight-related behaviors (diet, physical activity, sleep, media use) and parents’ weight-related parenting practices and empowerment. Data from 2 years, rather than three, were utilized to evaluate CHL due to the COVID-19 pandemic. We used mixed effects linear regression to compare relative differences during intervention vs. control periods (n = 1274 vs. 2476 children) in (1) mean change in child BMIz and modified BMIz, (2) the odds of meeting child health behavior recommendations, (3) mean change in parenting practices, and (4) mean change in parent empowerment. We also compared outcomes among parents who chose post-randomization to participate in PConnect vs. not (n = 55 vs. 443). Results During intervention periods (vs. control), children experienced greater increases in BMIz and modified BMIz (b = 0.06, 95% CI = 0.02,0.10; b = 0.07, 95% CI = 0.03, 0.12), yet were more likely to meet recommendations related to three of eight measured behaviors: sugar-sweetened beverage consumption (i.e., rarely consume; Odds Ratio (OR) = 1.5, 95% CI = 1.2,2.3), water consumption (i.e., multiple times per day; OR = 1.6, 95% CI = 1.2,2.3), and screen time (i.e., ≤1 hour/day; OR = 1.4, 95% CI = 1.0,1.8). No statistically significant differences for intervention (vs. control) periods were observed in parent empowerment or parenting practices. However, parents who enrolled in PConnect (vs. not) demonstrated greater increases in empowerment (b = 0.17, 95% CI = 0.04,0.31). Conclusions Interventions that emphasize parent engagement may increase parental empowerment. Intervention exposure was associated with statistically, but not clinically, significant increases in BMIz and increased odds of meeting recommendations for three child behaviors; premature trial suspension may explain mixed results. Trial registration ClinicalTrials.gov, NCT03334669 , Registered October 2017.

The increasing use of Point of Care Ultrasonography (POCUS) in medicine and healthcare prompted this pilot study, which aims to gain insight into the feasibility of online, self-directed POCUS training in the Physician Assistant (PA) curriculum. A mixed-method approach was used, gathering and analyzing data obtained from two cohorts of students in their didactic phase of training. Students completed a baseline survey, followed by the completion of several self-directed POCUS training modules, after which a post-survey was obtained. Seventy-six percent of the students had never used POCUS before. At the completion of the training, students demonstrated an increased level of confidence and comfort level using POCUS. The self-directed, self-paced, online format was not very favorable among the students. The recommendations for modifications, to incorporate live hands-on instruction were well received. It is important for PA programs to evaluate all aspects of a proposed POCUS training, including students’ perception, for a more meaningful learning experience.

Abstract Ring‐billed (Larus delawarensis) and herring (L. argentatus) gulls are numerous and widespread in North America. These gulls rank among the top 9 species for risk of bird‐aircraft collisions (hereafter strikes). The ubiquitous presence of gulls in urban coastal environments, including rooftop nesting behavior, are factors impacting strike risk. Our purpose was to assess gull response to a small uncrewed aircraft system (UAS) in hazing flights at night during the nest‐building phase. We hypothesized that nocturnal UAS operation, like nocturnal predator disturbance, might reduce gull numbers and, thus, strike risk to aircraft. In spring 2021, we conducted UAS treatments over target roofs at least once every hour from 2000 until 0200, weather permitting, for 15 min and over a 14‐day period for each site. The UAS flew directly above (~4 m) and then descended (~4 m/s) within 1 m of loafing gulls. No gulls interacted with the UAS and most flushed within 6 minutes. Generally, the first treatment of a night dispersed all gulls (min–max = 1–130 individuals) from the target roof for an extended period. Our operations were often grounded because of weather and our gull response data were limited because of few individuals present. We discuss our observations with particular attention to feasibility and possible implications such as shifting birds to other sites which, potentially, could be counterproductive for management.

Formaldehyde-free hair-straightening products are hair-smoothening solutions widely used by professional beauty salons. Formaldehyde-free hair straighteners do not technically contain formaldehyde; however, they contain other chemicals such as glyoxyloyl carbocysteine which releases formaldehyde upon contact with heat. Moreover, its by-product glyoxylate may convert to oxalate; both compounds have potential nephrotoxic effect. Here, we report a case of a 41-year-old woman who presented to the emergency room with weakness, nausea, vomiting, and stage 3 acute kidney injury (AKI) according to Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury staging shortly after exposure to formaldehyde-free hair-straightening product; other causes of AKI were excluded such as preceding acute illness, drug history, or other nephrotoxic agent exposure. On physical examination, the patient was pale, and her vital signs were normal. The urine microscopy and serologic workup were not indicative. Kidney core biopsy revealed interstitial edema, acute interstitial nephritis, and oxalate crystal nephropathy. Kidney function completely recovered after a short course of steroid therapy. In this case, AKI was a complication caused by exposure to hair-straightening products branded as formaldehyde free but actually containing other chemical products which release formaldehyde and other toxic chemicals when heated during the straightening procedure and may cause systemic toxicity, particularly kidney injury. Different cosmetic products are widely in use, but not all are under tight regulation, and therefore, it is important to raise the awareness among both medical teams and consumers of possible adverse health effects of different cosmetic products.

We call for journals to commit to requiring open data be archived in a format that will be simple and clear for readers to understand and use. If applied consistently, these requirements will allow contributors to be acknowledged for their work through citation of open data, and facilitate scientific progress.

Introduction Though community health workers (CHWs) have improved access to antenatal care (ANC) and institutional delivery in different settings, it is unclear what package and delivery strategy maximises impact.Methods This study reports a secondary aim of the Proactive Community Case Management cluster randomised trial, conducted between December 2016 and April 2020 in Mali. It evaluated whether proactive home visits can improve ANC access at a population level compared with passive site-based care. 137 unique village clusters, covering the entire study area, were stratified by health catchment area and distance to the nearest primary health centre. Within each stratum, clusters were randomly assigned to intervention or control arm. CHWs in intervention clusters proactively visited all homes to provide care. In the control clusters, CHWs provided the same services at their fixed community health post to care-seeking patients. Pregnant women 15–49 years old were enrolled in a series of community-based and facility-based visits. We analysed individual-level annual survey data from baseline and 24-month and 36-month follow-up for the secondary outcomes of ANC and institutional delivery, complemented with CHW monitoring data during the trial period. We compared outcomes between: (1) the intervention and control arms, and (2) the intervention period and baseline.Results With 2576 and 2536 pregnancies from 66 and 65 clusters in the intervention and control arms, respectively, the estimated risk ratios for receiving any ANC was 1.05 (95% CI 1.02 to 1.07), four or more ANC visits was 1.25 (95% CI 1.08 to 1.43) and ANC initiated in the first trimester was 1.11 (95% CI 1.02 to 1.19), relative to the controls; no differences in institutional delivery were found. However, both arms achieved large improvements in institutional delivery, compared with baseline. Monitoring data show that 19% and 2% of registered pregnancies received at least eight ANC contacts in the intervention and control arms, respectively. Six clusters, three from each arm had to be dropped in the last 2 years of the trial.Conclusions Proactive home visits increased ANC and the number of antenatal contacts at the clinic and community levels. ANC and institutional delivery can be increased when provided without fees from professional CHWs in upgraded primary care clinics.Trial registration number NCT02694055.