Moisture availability and groundwater recharge paced by orbital forcing over the past 750,000 years in the southwestern USA.

Quaternary climate changes are driven in part by variations in the distribution and strength of insolation due to orbital parameters. Continental climate variability is well documented for the most recent glacial-interglacial cycles, yet few records extend further back in time. Such records are critically needed to comprehensively assess the entire spectrum of natural climate variability against the backdrop of anthropogenic warming. Here, we apply uranium isotope geochronology to calcite deposits to date groundwater-table changes in Devils Hole cave, Nevada. The deposits record multi-meter groundwater-table fluctuations over the last 750,000 years, reflecting the long-term evolution of hydroclimate in this presently arid region. During periods between glacial or interglacial extremes, the water table responded sensitively to variations in 65°N summer insolation, likely caused by the increasing extent of North American ice sheets during cold period, which steered moisture-laden trajectories towards the southwestern USA. These orbitally-driven hydroclimatic changes are superimposed on a tectonically-driven long-term decline in the regional groundwater table observed prior to 438,000 ± 14,000 years ago.

Evaluating the risk of conflict on recent Ebola outbreaks in Guinea and the Democratic Republic of the Congo.

BACKGROUND: Reducing Ebola virus transmission relies on the ability to identify cases and limit contact with infected bodily fluids through biosecurity, safe sex practices, safe burial and vaccination. Armed conflicts can complicate outbreak detection and interventions due to widespread disruption to governments and populations. Guinea and the Democratic Republic of the Congo (DRC) have historically reported the largest and the most recent Ebola virus outbreaks. Understanding if conflict played a role in these outbreaks may help in identifying key risks factors to improve disease control. METHODS: We used data from a range of publicly available data sources for both Ebola virus cases and conflict events from 2018 to 2021 in Guinea and the DRC. We fitted these data to conditional logistic regression models using the Self-Controlled Case Series methodology to evaluate the magnitude in which conflict increased the risk of reported Ebola virus cases in terms of incidence rate ratio. We re-ran the analysis sub-nationally, by conflict sub-event type and tested any lagged effects. RESULTS: Conflict was significantly associated with an increased risk of reported Ebola virus cases in both the DRC and Guinea in recent outbreaks. The effect was of a similar magnitude at 1.88- and 1.98-times increased risk for the DRC and Guinea, respectively. The greatest effects (often higher than the national values) were found in many conflict prone areas and during protest/riot-related conflict events. Conflict was influential in terms of Ebola virus risk from 1 week following the event and remained important by 10 weeks. CONCLUSION: Extra vigilance is needed following protests and riot-related conflict events in terms of Ebola virus transmission. These events are highly disruptive, in terms of access to transportation and healthcare and are often in urban areas with high population densities. Additional public health messaging around these types of conflict events, relating to the risks and clinical symptoms may be helpful in reducing transmission. Future work should aim to further understand and quantify conflict severity and intensity, to evaluate dose-response relationships in terms of disease risk.

How new communication behaviors evolve: Androgens as modifiers of neuromotor structure and function in foot-flagging frogs.

How diverse animal communication signals have arisen is a question that has fascinated many. Xenopus frogs have been a model system used for three decades to reveal insights into the neuroendocrine mechanisms and evolution of vocal diversity. Due to the ease of studying central nervous system control of the laryngeal muscles in vitro, Xenopus has helped us understand how variation in vocal communication signals between sexes and between species is produced at the molecular, cellular, and systems levels. Yet, it is becoming easier to make similar advances in non-model organisms. In this paper, we summarize our research on a group of frog species that have evolved a novel hind limb signal known as 'foot flagging.' We have previously shown that foot flagging is androgen dependent and that the evolution of foot flagging in multiple unrelated species is accompanied by the evolution of higher androgen hormone sensitivity in the leg muscles. Here, we present new preliminary data that compare patterns of androgen receptor expression and neuronal cell density in the lumbar spinal cord - the neuromotor system that controls the hind limb - between foot-flagging and non-foot-flagging frog species. We then relate our work to prior findings in Xenopus, highlighting which patterns of hormone sensitivity and neuroanatomical structure are shared between the neuromotor systems underlying Xenopus vocalizations and foot-flagging frogs' limb movement and which appear to be species-specific. Overall, we aim to illustrate the power of drawing inspiration from experiments in model organisms, in which the mechanistic details have been worked out, and then applying these ideas to a non-model species to reveal new details, further complexities, and fresh hypotheses.

Fibrinolysis-Mediated Pathways in Acute Liver Injury.

Acute liver injury (ALI), that is, the development of reduced liver function in patients without preexisting liver disease, can result from a wide range of causes, such as viral or bacterial infection, autoimmune disease, or adverse reaction to prescription and over-the-counter medications. ALI patients present with a complex coagulopathy, characterized by both hypercoagulable and hypocoagulable features. Similarly, ALI patients display a profound dysregulation of the fibrinolytic system with the vast majority of patients presenting with a hypofibrinolytic phenotype. Decades of research in experimental acute liver injury in mice suggest that fibrinolytic proteins, including plasmin(ogen), plasminogen activators, fibrinolysis inhibitors, and fibrin(ogen), can contribute to initial hepatotoxicity and/or stimulate liver repair. This review summarizes major experimental findings regarding the role of fibrinolytic factors in ALI from the last approximately 30 years and identifies unanswered questions, as well as highlighting areas for future research.

Actl7b deficiency leads to mislocalization of LC8 type dynein light chains and disruption of murine spermatogenesis.

Actin-related proteins (Arps) are classified according to their similarity to actin and are involved in diverse cellular processes. ACTL7B is a testis-specific Arp, and is highly conserved in rodents and primates. ACTL7B is specifically expressed in round and elongating spermatids during spermiogenesis. Here, we have generated an Actl7b-null allele in mice to unravel the role of ACTL7B in sperm formation. Male mice homozygous for the Actl7b-null allele (Actl7b-/-) were infertile, whereas heterozygous males (Actl7b+/-) were fertile. Severe spermatid defects, such as detached acrosomes, disrupted membranes and flagella malformations start to appear after spermiogenesis step 9 in Actl7b-/- mice, finally resulting in spermatogenic arrest. Abnormal spermatids were degraded and levels of autophagy markers were increased. Co-immunoprecipitation with mass spectrometry experiments identified an interaction between ACTL7B and the LC8 dynein light chains DYNLL1 and DYNLL2, which are first detected in step 9 spermatids and mislocalized when ACTL7B is absent. Our data unequivocally establish that mutations in ACTL7B are directly related to male infertility, pressing for additional research in humans.

Cholera past and future in Nigeria: Are the Global Task Force on Cholera Control's 2030 targets achievable?

BACKGROUND: Understanding and continually assessing the achievability of global health targets is key to reducing disease burden and mortality. The Global Task Force on Cholera Control (GTFCC) Roadmap aims to reduce cholera deaths by 90% and eliminate the disease in twenty countries by 2030. The Roadmap has three axes focusing on reporting, response and coordination. Here, we assess the achievability of the GTFCC targets in Nigeria and identify where the three axes could be strengthened to reach and exceed these goals. METHODOLOGY/PRINCIPAL FINDINGS: Using cholera surveillance data from Nigeria, cholera incidence was calculated and used to model time-varying reproduction number (R). A best fit random forest model was identified using R as the outcome variable and several environmental and social covariates were considered in the model, using random forest variable importance and correlation clustering. Future scenarios were created (based on varying degrees of socioeconomic development and emissions reductions) and used to project future cholera transmission, nationally and sub-nationally to 2070. The projections suggest that significant reductions in cholera cases could be achieved by 2030, particularly in the more developed southern states, but increases in cases remain a possibility. Meeting the 2030 target, nationally, currently looks unlikely and we propose a new 2050 target focusing on reducing regional inequities, while still advocating for cholera elimination being achieved as soon as possible. CONCLUSION/SIGNIFICANCE: The 2030 targets could potentially be reached by 2030 in some parts of Nigeria, but more effort is needed to reach these targets at a national level, particularly through access and incentives to cholera testing, sanitation expansion, poverty alleviation and urban planning. The results highlight the importance of and how modelling studies can be used to inform cholera policy and the potential for this to be applied in other contexts.

A chromosome-length genome assembly and annotation of blackberry (Rubus argutus, cv. "Hillquist").

Blackberries (Rubus spp.) are the fourth most economically important berry crop worldwide. Genome assemblies and annotations have been developed for Rubus species in subgenus Idaeobatus, including black raspberry (R. occidentalis), red raspberry (R. idaeus), and R. chingii, but very few genomic resources exist for blackberries and their relatives in subgenus Rubus. Here we present a chromosome-length assembly and annotation of the diploid blackberry germplasm accession "Hillquist" (R. argutus). "Hillquist" is the only known source of primocane-fruiting (annual-fruiting) in tetraploid fresh-market blackberry breeding programs and is represented in the pedigree of many important cultivars worldwide. The "Hillquist" assembly, generated using Pacific Biosciences long reads scaffolded with high-throughput chromosome conformation capture sequencing, consisted of 298 Mb, of which 270 Mb (90%) was placed on 7 chromosome-length scaffolds with an average length of 38.6 Mb. Approximately 52.8% of the genome was composed of repetitive elements. The genome sequence was highly collinear with a novel maternal haplotype-resolved linkage map of the tetraploid blackberry selection A-2551TN and genome assemblies of R. chingii and red raspberry. A total of 38,503 protein-coding genes were predicted, of which 72% were functionally annotated. Eighteen flowering gene homologs within a previously mapped locus aligning to an 11.2 Mb region on chromosome Ra02 were identified as potential candidate genes for primocane-fruiting. The utility of the "Hillquist" genome has been demonstrated here by the development of the first genotyping-by-sequencing-based linkage map of tetraploid blackberry and the identification of possible candidate genes for primocane-fruiting. This chromosome-length assembly will facilitate future studies in Rubus biology, genetics, and genomics and strengthen applied breeding programs.

Association between Conflict and Cholera in Nigeria and the Democratic Republic of the Congo.

Cholera outbreaks contribute substantially to illness and death in low- and middle-income countries. Cholera outbreaks are associated with several social and environmental risk factors, and extreme conditions can act as catalysts. A social extreme known to be associated with infectious disease outbreaks is conflict, causing disruption to services, loss of income, and displacement. To determine the extent of this association, we used the self-controlled case-series method and found that conflict increased the risk for cholera in Nigeria by 3.6 times and in the Democratic Republic of the Congo by 2.6 times. We also found that 19.7% of cholera outbreaks in Nigeria and 12.3% of outbreaks in the Democratic Republic of the Congo were attributable to conflict. Our results highlight the value of providing rapid and sufficient assistance during conflict-associated cholera outbreaks and working toward conflict resolution and addressing preexisting vulnerabilities, such as poverty and access to healthcare.

Identification of a Quaternary rock avalanche deposit (Central Apennines, Italy): Significance for recognition of fossil catastrophic mass-wasting.

Whereas deposits of extremely-rapid, 'catastrophic' mass wastings >105 m3 in volume (for example, the Marocche di Dro rock avalanche in the Southern Alps and the Flims rockslide in the Western Alps) are easily recognized by their sheer mass and blocky surface, the identification of fossil catastrophic mass wastings partly removed by erosion must be based on deposit characteristics. Herein, a 'fossil' (pre-last glacial) rock avalanche, previously interpreted as either a till or debris flow, is described. The deposit, informally called 'Rubble Breccia', is located in the intramontane Campo Imperatore halfgraben that is bounded by a master fault with up to ca 900 m topographic throw. Based on documentation from field to thin section, and by comparative analysis with post-glacial rock avalanches, tills and debris flows, the Rubble Breccia is reinterpreted as a rock avalanche. The Rubble Breccia consists of an extremely-poorly sorted, disordered mixture of angular clasts from sand to block size. Many clasts show fitted subclast boundaries in crackle, jigsaw and mosaic fabrics, as diagnostic of catastrophic mass wasting deposits. Intercalated layers of angular to well-rounded clasts of coarse sand to fine pebble size, and deformed into open to recumbent folds, may represent shear belts folded during terminal avalanche propagation. The clast spectrum of the Rubble Breccia - mainly shallow-water bioclastic limestones, Saccocoma wackestones and other deep-water limestones and dolostones - is derived from the front range along the northern margin of the basin. Calcite cement found within the Rubble Breccia was dated with the U/Th disequilibrium method to 124.25 ± 2.76 ka bp, providing an ante-quam age constraint to the rock avalanche event. Because catastrophic mass wasting is a common erosional process, fossil deposits thereof should be more widespread than have been identified to date, although this may be a consequence of misidentification. The criteria outlined here provide a template to identify fossil catastrophic mass wasting deposits of any age.

Epistemic trauma and transracial adoption: Author(iz)ing folkways of knowledge and healing.

BACKGROUND: Despite contested definitions, trauma is often conceptualized as an event that shocks or overloads human systems, shaping memory and meanings as the body and mind attempt to cope and survive. Adoption is often the presumed redress for childhood trauma. Thus, few scholars have examined how, or if, some conditions of adoption or the status itself might involve unique traumas or adversities. OBJECTIVE: In this paper, I argue that the condition of being transracially adopted can represent intersectional minoritized statuses, which in turn activate potentially distinct formations of epistemic trauma- structurally and relationally transmitted harms to a person as a knower and to their capacities for claiming, making sense of, and healing through their lived experiences. PARTICIPANTS AND SETTING: I draw from my personal and professional standpoints as a black, mixed-race, woman who was transracially adopted from public foster care as an infant, became a child welfare caseworker and later, a child welfare scholar. METHODS: Using a critical and reflexive autoethnographic method I ask how theories of epistemic injustice might help to highlight conditions tied to the status "transracial adoptee" that distinguish adoption-specific trauma. By reflexively analyzing my experiences in the context of extant theory and research, this paper brings theories of epistemic injustice into conversation with an emic perspective on adoption. RESULTS: In my experience, "transracial adoptee" and "mixed race" operated as statuses that occasioned epistemic injustices. I propose these conditions can become traumatic when they chronically and structurally disenfranchise claiming and cultivating folkways essential to one's healing and resilience across the life course. CONCLUSIONS: This paper is a call to invest in advancing epistemologies of adoption and theories of trauma that are anchored within diverse adoption experiences. I also invite future scholarship to explore epistemic injustice in adoption as trauma, and to identify and disrupt the many spaces in which it may be enacted culturally, relationally, familially, and in a society through its laws, policies, practices, and scientific knowledge.

Accessing sub-national cholera epidemiological data for Nigeria and the Democratic Republic of Congo during the seventh pandemic.

BACKGROUND: Vibrio cholerae is a water-borne pathogen with a global burden estimate at 1.4 to 4.0 million annual cases. Over 94% of these cases are reported in Africa and more research is needed to understand cholera dynamics in the region. Cholera data are lacking, mainly due to reporting issues, creating barriers for widespread research on cholera epidemiology and management in Africa. MAIN BODY: Here, we present datasets that were created to help address this gap, collating freely available sub-national cholera data for Nigeria and the Democratic Republic of Congo. The data were collated from a variety of English and French publicly available sources, including the World Health Organization, PubMed, UNICEF, EM-DAT, the Nigerian CDC and peer-reviewed literature. These data include information on cases, deaths, age, gender, oral cholera vaccination, risk factors and interventions. CONCLUSION: These datasets can facilitate qualitative, quantitative and mixed methods research in these two high burden countries to assist in public health planning. The data can be used in collaboration with organisations in the two countries, which have also collected data or undertaking research. By making the data and methods available, we aim to encourage their use and further data collection and compilation to help improve the data gaps for cholera in Africa.

Analysis of a Multi-Environment Trial for Black Raspberry (Rubus occidentalis L.) Quality Traits.

U.S. black raspberry (BR) production is currently limited by narrowly adapted, elite germplasm. An improved understanding of genetic control and the stability of pomological traits will inform the development of improved BR germplasm and cultivars. To this end, the analysis of a multiple-environment trial of a BR mapping population derived from a cross that combines wild ancestors introgressed with commercial cultivars on both sides of its pedigree has provided insights into genetic variation, genotype-by-environment interactions, quantitative trait loci (QTL), and QTL-by-environment interactions (QEI) of fruit quality traits among diverse field environments. The genetic components and stability of four fruit size traits and six fruit biochemistry traits were characterized in this mapping population following their evaluation over three years at four distinct locations representative of current U.S. BR production. This revealed relatively stable genetic control of the four fruit size traits across the tested production environments and less stable genetic control of the fruit biochemistry traits. Of the fifteen total QTL, eleven exhibited significant QEI. Closely overlapping QTL revealed the linkage of several fruit size traits: fruit mass, drupelet count, and seed fraction. These and related findings are expected to guide further genetic characterization of BR fruit quality, management of breeding germplasm, and development of improved BR cultivars for U.S. production.

Improving Patient Selection and Prioritization for Hospital at Home Through Predictive Modeling.

Hospital at home is designed to offer patients hospital level care in the comfort of their own home. The process by which clinicians select eligible patients that are clinically and socially appropriate for this model of care requires labor-intensive manual chart reviews. We addressed this problem by providing a predictive model, web application, and data pipeline that produces an eligibility score based on a set of clinical and social factors that influence patients' success in the program. Providers used this predictive model to prioritize the order in which they perform chart reviews and patient screenings. Training performance area under the curve (AUC) was 0.77. Testing 'in production' had an AUC of 0.75. Admission criteria in training rapidly changed over the course of the study due to the novelty of the clinical model. The current algorithm successfully identified many inconsistencies in enrollment and has streamlined the process of patient identification.

The impact of social and environmental extremes on cholera time varying reproduction number in Nigeria.

Nigeria currently reports the second highest number of cholera cases in Africa, with numerous socioeconomic and environmental risk factors. Less investigated are the role of extreme events, despite recent work showing their potential importance. To address this gap, we used a machine learning approach to understand the risks and thresholds for cholera outbreaks and extreme events, taking into consideration pre-existing vulnerabilities. We estimated time varying reproductive number (R) from cholera incidence in Nigeria and used a machine learning approach to evaluate its association with extreme events (conflict, flood, drought) and pre-existing vulnerabilities (poverty, sanitation, healthcare). We then created a traffic-light system for cholera outbreak risk, using three hypothetical traffic-light scenarios (Red, Amber and Green) and used this to predict R. The system highlighted potential extreme events and socioeconomic thresholds for outbreaks to occur. We found that reducing poverty and increasing access to sanitation lessened vulnerability to increased cholera risk caused by extreme events (monthly conflicts and the Palmers Drought Severity Index). The main limitation is the underreporting of cholera globally and the potential number of cholera cases missed in the data used here. Increasing access to sanitation and decreasing poverty reduced the impact of extreme events in terms of cholera outbreak risk. The results here therefore add further evidence of the need for sustainable development for disaster prevention and mitigation and to improve health and quality of life.

Drought-related cholera outbreaks in Africa and the implications for climate change: a narrative review.

Africa has historically seen several periods of prolonged and extreme droughts across the continent, causing food insecurity, exacerbating social inequity and frequent mortality. A known consequence of droughts and their associated risk factors are infectious disease outbreaks, which are worsened by malnutrition, poor access to water, sanitation and hygiene and population displacement. Cholera is a potential causative agent of such outbreaks. Africa has the highest global cholera burden, several drought-prone regions and high levels of inequity. Despite this, research on cholera and drought in Africa is lacking. Here, we review available research on drought-related cholera outbreaks in Africa and identify a variety of potential mechanisms through which these outbreaks occurred, including poor access to water, marginalization of refugees and nomadic populations, expansion of informal urban settlements and demographic risks. Future climate change may alter precipitation, temperature and drought patterns, resulting in more extremes, although these changes are likely to be spatially heterogeneous. Despite high uncertainty in future drought projections, increases in drought frequency and/or durations have the potential to alter these related outbreaks into the future, potentially increasing cholera burden in the absence of countermeasures (e.g. improved sanitation infrastructure). To enable effective planning for a potentially more drought-prone Africa, inequity must be addressed, research on the health implications of drought should be enhanced, and better drought diplomacy is required to improve drought resilience under climate change.

Exception-Status Listing: A Critical Pathway to Heart Transplantation for Adults With Congenital Heart Diseases.

Adults with congenital heart diseases may not be candidates for conventional therapies to control ventricular systolic dysfunction, including mechanical circulatory support, which moves potential heart-transplantation recipients to a listing status of higher priority. This results in longer waitlist times and greater mortality rates. Exception-status listing allows a pathway for this complex and anatomically heterogenous group of patients to be listed for heart transplantation at appropriately high listing status. Our study queried the United Network for Organ Sharing registry to evaluate trends in the use of exception-status listing among adults with congenital heart diseases awaiting heart transplantation. Uptrend in the use of exception-status listing precedes the new allocation system, but it has been greatest since changes were made in the allocation system. It continues to remain a vital pathway for adults with congenital heart disease (whose waitlist mortality rates are often not characterized adequately by using the waitlist-status criteria) timely access to heart transplantation.

New Drug Formulary Management and Utilization: Evidence in Sex, Race, and Ethnicity: 2019-2020.

BACKGROUND: It is well established that females and persons of racial and ethnic minorities are frequently underrepresented in clinical trials. These disparities are potentially important aspects of evidence-based formulary management and drug utilization review (DUR) processes. OBJECTIVE: The purpose of this study was to review the demographic composition of pivotal trials and post-approval study requirements for recent FDA-approved drugs, analyzing the representation of minority groups and its generalizability to the US population or corresponding disease state. METHODS: Drugs approved between July 2019 and June 2020 were identified and demographic data including race, ethnicity, and sex was extracted from their pivotal trials. Demographic data was compared to US demographics and/or the disease state demographics for the respective approved drug. RESULTS: There were a total of 85 drugs and 142 pivotal trials included in the study. Compared to the estimated US population, the minority groups with a statistically significant underrepresentation across all pivotal trials included Black or African Americans and American Indian or Alaska Natives. The Hispanic/Latinx population had a statistically significant underrepresentation in 55.4% of trials. Females had a statistically significant underrepresentation in 21.2% of trials when compared to the disease state demographics of the respective approved drug. CONCLUSION AND RELEVANCE: Persons of minorities are underrepresented in the generation of evidence of safety and efficacy for many new drugs. Formulary management and DUR offer an integrated strategic opportunity for the clinical community to formally and carefully consider the data on sex, race, and ethnicity to address disparities in health care.

Adolescent high-fructose corn syrup consumption leads to dysfunction in adult affective behaviors and mesolimbic proteins in male Sprague-Dawley rats.

Adolescence is a critical period of development, during which the brain undergoes rapid maturation. Problematically, adolescents are the top consumers of high fructose corn syrup (HFCS) sweetened beverages and snacks, which may have neurodevelopmental consequences. While HFCS consumption has been linked to an increased likelihood of obesity and other physical health impairments, the link between HFCS and persistent behavioral changes is not yet fully established. The present study aimed to assess whether adolescent HFCS consumption could lead to alterations in adult behaviors and protein expression, following cessation. Adolescent HFCS-exposure contributed to deficits in learning and motivation on an effort-related T-Maze procedure, as well as increased immobility time in the forced swim paradigm during adulthood. Molecularly, protracted decreases in accumbal dopamine D1 and D2 receptors and protein kinase G (PKG), as well as increases in tyrosine hydroxylase and GluA2 receptor subunits, were observed following HFCS-exposure. Taken together, these data suggest that adolescent HFCS-consumption leads to protracted dysfunction in affective behaviors and alterations in accumbal proteins which persist following cessation of HFCS-consumption.