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"The COVID-19 pandemic has caused significant changes in various sectors of human life and triggered significant and rapid cultural changes within organizations. Because the virus has caused a long-lasting pandemic, many companies have had to change their strategies and culture within their organization. The type of research taken is a qualitative descriptive approach with conceptual data types, and the data source used is secondary data based on previous research results or notes. The results of this research show that the organizational culture changes that occurred during the COVID-19 pandemic include the implementation of remote work, emphasis on employee health and safety, changes in leadership style, increased internal and external communication, as well as innovation and digitization. Although these changes pose challenges for organizations, they also present opportunities to improve and strengthen organizations in the future."

Gender gaps in academic performance have been reported at a variety of educational levels including several national standardized exams for medical education, with men scoring higher than women. These gaps potentially impact medical school acceptance and residency matching and may be influenced by curricular design. Performance data for our 4-year integrated hybrid curriculum, which features a large proportion of active learning, revealed a gender gap with men performing better early in the curriculum and on the first national standardized exam. This gap in performance almost entirely disappeared for years 2–4 of the curriculum and the second national standardized exam.

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non–small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells—such as M2 tumor-associated macrophages (TAM)—thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti–PD-1–resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti–PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

There is a paucity of data describing patients' expectations of goals of palliative radiotherapy (RT) and overall prognosis.To explore patients' perceptions of and preferences for communication surrounding goals of palliative RT and cancer prognosis.We conducted a qualitative study utilizing semi-structured interviews with seventeen patients with either bone or lung metastases receiving their first course of palliative RT at a comprehensive cancer center. All patient interviews were recorded, transcribed verbatim, and thematically analyzed.Themes of goals of palliative RT centered on either restoration, such as through improving quality of life or minimizing pain, or on a desire to combat cancer by eliminating tumor. While most patients perceived that palliative RT would palliate symptoms but not cure their cancer, some patients believed that the goal of palliative RT was to cure. Themes that emerged surrounding patients' understanding of prognosis and what lies ahead included uncertainty and apprehension about the future, a focus on additional treatment, and confronting mortality. Most patients preferred to receive information about goals of treatment and prognosis from their doctors, including radiation oncologists, rather than other members of the medical team. Patients also expressed a desire for written patient education materials on palliative RT.Unclear perceptions of goals of treatment and prognosis may motivate some patients to pursue unnecessarily aggressive cancer treatments. Patients desire prognostic information from their doctors, including radiation oncologists, who are important contributors to goals of care discussions and may improve patient understanding and well-being by using restorative rather than combat-oriented language.

Enduring questions about equity are front and center at this watershed moment in health care and public health. Inequities that became evident in the COVID-19 pandemic in 2020 have highlighted long-standing disparities in health by race and ethnicity. Current crises require examining and reorienting the systems that have, for decades, produced these health inequities; yet, public health and health care leaders are inadequately prepared to respond. The authors offer an equity-centered leadership framework to support the development of visionary leaders for tomorrow. This framework for leadership development programs interweaves traditional leadership and equity, diversity, and inclusion domains in both conceptual knowledge and skills-based teaching for health care and public health leaders, grouping competencies and skills into 4 domains: personal, interpersonal, organizational, and community and systems. A framework such as this will equip leaders with the mindset and skill set to challenge the paradigms that lead to inequity and health disparities.

Littorinid snails are present in most coastal areas globally, playing a significant role in the ecology of intertidal communities. Laevilitorina is a marine gastropod genus distributed exclusively in the Southern Hemisphere, with 21 species reported from South America, the sub-Antarctic islands, Antarctica, New Zealand, Australia and Tasmania. Here, an updated database of 21 species generated from a combination of sources is presented: 1) new field sampling data; 2) published records; 3) the Global Biodiversity Information Facility (GBIF) and The Atlas of Living Australia (ALA), to provide a comprehensive description of the known geographic distribution of the genus and detailed occurrences for each of the 21 species. The database includes 813 records (occurrences), 53 from field sampling, 174 from the literature, 128 from GBIF, and 458 from ALA. West Antarctica had the highest species richness (8 species), followed by sub-Antarctic islands of New Zealand (4 species) and the south-east shelf of Australia (4 species). The provinces of Magellan, New Zealand South Island, and sub-Antarctic Islands of the Indian Ocean include two species each. This study specifically highlights reports of L. pygmaea and L. venusta, species that have been almost unrecorded since their description. Recent advances in molecular studies of L. caliginosa showed that this species does not correspond to a widely distributed taxon, but to multiple divergent lineages distributed throughout the Southern Ocean. Ongoing molecular and taxonomic studies are necessary for a better understanding of the diversity and biogeography of this genus.

Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group (in/i = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSElt;8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

BACKGROUND: Stretching exercises increase the joint range of motion (ROM) and depend on the skeletal tissues' exposition-time to stretch. However, it is unclear how a long stretching time affects the muscle-tendon unit's passive mechanical properties. AIM: This study aimed to analyze changes in the triceps surae muscle-tendon unit’s passive mechanical properties before and after a 10-minute passive stretching protocol. METHOD: Thirty healthy participants (26.57 ± 3.82 years old) were allocated into a control group (n=15), who did not perform any intervention, and to an experimental group (n=15), who performed one bout of a 10-minute ankle plantar flexor passive static stretching. Ankle ROM, plantar flexor passive torque, and myotendinous junction displacement were evaluated pre-intervention, immediately after, and 15, 30, 45, and 60 minutes after the end of the intervention. The stiffnesses of the muscle-tendon unit, muscle, and tendon were calculated for all moments. A generalized estimating equation test was performed to compare groups and moments. RESULTS: The experimental group increased the ROM (p

Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein. How C9orf72 haploinsufficiency contributes to disease has not been resolved. Here we identify the synapsin family of synaptic vesicle proteins, the most abundant group of synaptic phosphoproteins, as novel interactors of C9orf72 at synapses and show that C9orf72 plays a cell-autonomous role in the regulation of excitatory synapses. We mapped the interaction of C9orf72 and synapsin to the N-terminal longin domain of C9orf72 and the conserved C domain of synapsin, and show interaction of the endogenous proteins in synapses. Functionally, C9orf72 deficiency reduced the number of excitatory synapses and decreased synapsin levels at remaining synapses in vitro in hippocampal neuron cultures and in vivo in the hippocampal mossy fibre system of C9orf72 knockout mice. Consistent with synaptic dysfunction, electrophysiological recordings identified impaired excitatory neurotransmission and network function in hippocampal neuron cultures with reduced C9orf72 expression, which correlated with a severe depletion of synaptic vesicles from excitatory synapses in the hippocampus of C9orf72 knockout mice. Finally, neuropathological analysis of post-mortem sections of C9ALS/FTD patient hippocampus with C9orf72 haploinsufficiency revealed a marked reduction in synapsin, indicating that disruption of the interaction between C9orf72 and synapsin may contribute to ALS/FTD pathobiology. Thus, our data show that C9orf72 plays a cell-autonomous role in the regulation of neurotransmission at excitatory synapses by interaction with synapsin and modulation of synaptic vesicle pools, and identify a novel role for C9orf72 haploinsufficiency in synaptic dysfunction in C9ALS/FTD.

As the coronavirus disease (COVID-19) pandemic led to a global health crisis, there were limited treatment options and no prophylactic therapies for those exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma is quick to implement, potentially provides benefits, and has a good safety profile. The therapeutic potential of COVID-19 convalescent plasma (CCP) is likely mediated by antibodies through direct viral neutralization and Fc-dependent functions such as a phagocytosis, complement activation, and antibody-dependent cellular cytotoxicity. In the United States, CCP became one of the most common treatments with more than a half million units transfused despite limited efficacy data. More than a dozen randomized trials now demonstrate that CCP does not provide benefit for those hospitalized with moderate to severe disease. However, similar to other passive antibody therapies, CCP is beneficial for early disease when provided to elderly outpatients within 72 hours after symptom onset. Only high-titer CCP should be transfused. CCP should also be considered for immunosuppressed patients with COVID-19. CCP collected in proximity, by time and location, to the patient may be more beneficial because of SARS-CoV-2 variants. Additional randomized trial data are still accruing and should be incorporated with other trial data to optimize CCP indications.

Anticoagulation requires urgent reversal in cases of life-threatening bleeding or invasive procedures.Network meta-analysis for comparing the safety and efficacy of warfarin reversal strategies including plasma and prothrombin complex concentrates (PCCs).Seven studies including 594 subjects using reversal agents plasma, 3-factor-PCC (Uman Complex and Konyne), and 4-factor-PCC (Beriplex/KCentra, Octaplex, and Cofact) met inclusion criteria. Compared with plasma, patients receiving Cofact probably have a higher rate of international normalized ratio (INR) correction (risk difference [RD] 499 more per 1000 patients, 95% confidence interval [CI], 176-761, low certainty[LC]); higher reversal of bleeding (323 more per 1000 patients, 11-344 more, LC); and fewer transfusion requirements (0.96 fewer units, 1.65-0.27 fewer, LC). Patients receiving Beriplex/KCentra probably have a higher rate of INR correction (476 more per 1000 patients, 332-609 more, LC); higher reversal of bleeding (127 more per 1000 patients, 43 fewer to 236 more); and similar transfusion requirements (0.01 fewer units, 0.31 fewer to 0.28 more, high/moderate certainty). Patients receiving Octaplex probably have a higher rate of INR correction (RD 579 more per 1000 patients, 189-825 more, LC).PCCs probably provide an advantage in INR reversal compared to plasma. There was no added risk of adverse events with PCCs.

Quaternary glaciations severely altered landscape/seascape at high latitudes and had major consequences on species geographical ranges, population sizes, genetic differentiation and speciation rates. The Magellan province in southern South America, constitutes an interesting area to evaluate the effect of glaciations over near-shore marine benthic organisms. Existing data have showed clear signatures of population genetic bottlenecks during glacial maxima followed by recent recolonizations and expansions during the interglacial. Here, we present new population-based analyses in species of the patellogastropod genus Nacella (N. deaurata, N. magellanica, and N. mytilina). The species N. magellanica and N. deaurata inhabit rocky ecosystems while N. mytilina lives closely associated with kelps. The analyzed species exhibit narrow bathymetric ranges and consequently should have been severely affected by recurrent glacial cycles. We performed phylogeographic and demographic analyses in Nacella species including different localities across their respective distributions in the Magellan province including the Falkland/Malvinas Islands (F/M). Genetic analyses showed that all Nacella species exhibited low levels of genetic diversity, the presence of single dominant broadly distributed haplotypes, lack of correlation between geographical and genetic distance, and recent demographic growths, which are evidence supporting rapid postglacial expansions. Such results may have been facilitated by larval and/or rafting-mediated dispersal following the Cape Horn Current System. The three species showed strong and significant differentiation between F/M and southern Pacific margin (SPM) populations including localities across the Strait of Magellan and Cape Horn. Haplotype genealogies and mismatch analyses recognized older and more complex demographic histories in the F/M than in South America. Different glaciological histories between SPM and F/M may be responsible of the marked phylogeographic structure in the analyzed species of Nacella. Alternatively, as previously proposed, the F/M represent a glacial refugium for Nacella species (sink area), as well as a secondary contact zone where endemic haplotypes are found together with recently arrived South American ones. Historical and contemporary processes, contrasting glacial histories between the analyzed areas, as well as life history traits of the analyzed organisms are main factors explaining current phylogeographic patterns of shallow Magellan marine benthic organisms.

Vanadium doped indium sulfide, In2S3:V, is studied as a potential absorber material for intermediate band solar cells. Based on electronic considerations, it is usually assumed that V occupies octahedrally coordinated In sites, although geometrical considerations would favor tetrahedral In sites. In this study, we therefore combined experimental X-ray diffraction and X-ray absorption spectroscopy with ab initio theoretical calculations of both α and β phase to elucidate the incorporation of V in In2S3:V thin films grown with different V content and different growth temperatures. Comparing shape and position of the measured and calculated X-ray absorption edge of V, comparing experimentally determined and calculated V-S bond lengths, and evaluating the calculated heat of solution of V on different lattice sites all indicate that V is incorporated on octahedral rather than tetrahedral sites in the In2S3 matrix. For this material system, the electronic benefit of octahedral coordination thus outweighs the mechanical stress of the associated lattice relaxation. Finally, we studied the electronic structure of V-substituted α-In2S3 using hybrid density functional calculations and find that for a concentration of 1.9 at%, V on octahedrally coordinated In sites forms an empty intermediate band isolated from valence and conduction bands. By increasing the V content to 3.8 at%, however, the gap between intermediate band and conduction band closes, which results in a reduction of the band gap. This differs from the electronic structure calculated for β-In2S3:V and clearly demonstrates that both crystal structure and V incorporation site affect the resulting electronic material properties.

BackgroundHIV pre-exposure prophylaxis (PrEP) is key to HIV transmission elimination but implementation is challenging and under-researched. We undertook a process evaluation of the first two years of a national PrEP programme to explore barriers and facilitators to implementation and to develop recommendations to improve implementation, focussing on PrEP uptake and initiation.MethodsStage 1 involved semi-structured telephone interviews and focus groups (09/2018-07/2019) with geographically and demographically diverse patients seeking/using/declining/stopping PrEP (n=39), sexual healthcare professionals (n= 54), community-based organisation service users (n=9) and staff (n=15) across Scotland. We used deductive thematic analysis, to derive and then map key barriers and facilitators to priority areas that experts agreed would enhance initiation and uptake. In Stage 2 we used analytic tools from implementation science to systematically generate evidence-based, theoretically-informed recommendations to enhance uptake and initiation of PrEP.ResultsBarriers and facilitators were multi-levelled and interdependent. Barriers included the rapid pace of implementation without additional resource, and a lack of familiarity with PrEP prescribing. Facilitators included opportunities for acquisition of practice-based knowledge and normalisation of initiation activities. We refined our 68 “long-list” recommendations to 41 using expert input and the APEASE criteria. Examples include: provision of PrEP in diverse settings to reach all in need; co-produced, culturally sensitive training resources for healthcare professionals, with focused content on non-daily dosing; meaningful collaborative working across all stakeholders.ConclusionsThese evidence-based, theory informed recommendations provide a robust framework for optimising PrEP uptake and initiation in diverse settings to ensure PrEP reaches all who may benefit.Summary for table of contentsZero new HIV infections could become a reality if HIV pre-exposure prophylaxis (PrEP) programmes are successfully implemented but the World Health Organisation recognizes that large scale roll out is challenging.We used implementation science research tools in novel ways to evaluate one of the world’s first national PrEP programmes, to develop evidence-based recommendations for use across a range of settings to improve PrEP uptake and initiation.Adopting these recommendations could enable governments and societies to better address HIV prevention goals.

Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a “nihilism guard.” More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.

The conception of “floral strips” is a strategy to provide more and different food sources for pollinators. The impact of “homogeneous” Phacelia tanacetifolia (“Phacelia”) and “heterogeneous” (flower mix) food sources on the enzyme activity of bumblebees (Bombus terrestris) and honeybees (Apis mellifera) under urban conditions has not been reported. Organisms responding to challenging environmental conditions are known to exhibit increases in oxidative stress parameters which in turn affect both physiological and metabolic parameters. A field study was conducted in Berlin-Dahlem, Germany, using the response of the “marker” enzyme superoxide dismutase (SOD) on food sources for assessment. SOD data is also shown from the wild bee Megachile rotundata (Fabricius 1787), obtained from three different locations in the federal state Brandenburg, Germany. The results demonstrate that the enzyme activity of SOD significantly increased in bumblebees visiting the flower mix compared to the Phacelia. The experimental approach had individual effects at the level of the species, bumblebees and honeybees, respectively. The activity of the biomarker SOD could be successfully used to assess the effects of the compositions of homogeneous and heterogeneous flower fields. “Advancement of women” of the Albrecht Daniel Thaer-Institute (ADTI), Faculty of Life Sciences, Humboldt-University of Berlin

Supplementary Figures and Tables

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non–small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells—such as M2 tumor-associated macrophages (TAM)—thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti–PD-1–resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti–PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

BackgroundPlatelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion.Study designAn open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality.ResultsBy modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio=0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p= .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p= .151; odds ratio=0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p= .256); and allergic TR were significantly less with PRPC (p= .006). PC and RBC use were not increased with PRPC.DiscussionPRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Each year the AABB Clinical Transfusion Medicine Committee (CTMC) procures a synopsis highlighting new, important, and clinically relevant studies in the field of transfusion medicine (TM). This has been made available as a publication in Transfusion since 2018.CTMC members reviewed and identified original manuscripts covering TM-related topics published electronically (ahead-of-print) or in print from December 2020 to December 2021. Selection of publications was discussed at committee meetings and chosen based on perceived relevance and originality. Next, committee members worked in pairs to create a synopsis of each topic, which was then reviewed by additional committee members. The first and senior authors assembled the final manuscript. Although this synopsis is extensive, it is not exhaustive, and some articles may have been excluded or missed.The following topics are included: blood products; convalescent plasma; donor collections and testing; hemoglobinopathies; immunohematology and genomics; hemostasis; patient blood management; pediatrics; therapeutic apheresis; and cell therapy.This synopsis highlights and summarizes recent key developments in TM and may be useful for educational purposes.

La deposición de nutrientes por vía atmosférica tiene graves impactos sobre la ecología de bosques y cuerpos de agua templados. Sin embargo, su importancia en cuerpos de agua neotropicales casi no ha sido estudiada. En este artículo se cuantifica la contribución de nitrógeno inorgánico disuelto (NID, [NO3--N + NH4+-N]) y fósforo inorgánico soluble (FIS, [PO4-3-P]) depositados en bulto sobre superficies húmedas por vía atmosférica hacia el lago Atitlán (Guatemala). Las cargas estimadas de NID y FIS consecuencia de la deposición atmosférica directa (depositada sobre la superficie del lago) fueron de 151.2 ton/año y 5.6 ton/año, respectivamente. Con estos resultados, se estima que el aporte de FIS por deposición atmosférica al lago Atitlán es comparable al de sus principales ríos tributarios, y de casi el doble para el ingreso de NID. Las estimaciones para el lago Atitlán son mayores que lo reportado para otros lagos. Nuestro estudio proporciona información básica para entender la eutrofización del lago Atitlán, enfatizado en la importancia de la deposición atmosférica como contribuyente al deterioro de este cuerpo de agua. Además, demuestra la necesidad de extender este tipo de estudio a otras cuencas neotropicales y la importancia de minimizar este impacto.

To evaluate the accuracy and repeatability of the Tono-Pen XL™, TonoVet® and TonoVet Plus® tonometers by manometric evaluation, and to establish adjustment equations for intraocular pressure (IOP) estimates in rabbits.Rabbits.A postmortem study was conducted on seven rabbit eyes to verify the correlation between manometry and tonometry with an artificial incremental increase in IOP from 5 and 60 mmHg. A clinical study was conducted to evaluate accuracy and to establish reference values for the species, with measurement of IOP in 17 animals, for 2 consecutive days, with the same tonometers and calibrations used in the postmortem evaluations.There were strong linear trends for all evaluated tonometers. In the in-vivo evaluation, the mean IOP values were: 14.23 ± 1.75 (Tono-Pen XL™); 13.89 ± 2.07 (TonoVet® calibration mode 'd'); 8.88 ± 1.24 (TonoVet calibration mode 'p'); 18.59 ± 1.94 (Tonovet Plus®). There was a significant difference in the two evaluation times for the two TonoVet® calibration modes. The adjustment equations generated from the manometry for the evaluated tonometers were: Y = 0.2570X + 2.219 (Tono-Pen XL™), Y = 0.2289X + 2.389 (TonoVet® 'd'), Y = 0.4043X + 4.062 (TonoVet® 'p'), Y = 0.1233X + 0.3644 (TonoVet Plus®) (X is device-estimated IOP).All evaluated tonometers were well correlated with the manometry, with an underestimation of IOP by all devices. Applying adjustment formulas may compensate for systematic errors. TonoVet Plus® was well tolerated, and showed better repeatability and reliability in successive evaluations.

In 2016, the National Academies of Science, Engineering and Medicine called for the development of a National Trauma Research Action Plan. The Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. Given the public health burden of injuries to the central nervous system, neurotrauma was one of 11 panels formed to address this recommendation with a gap analysis and generation of high-priority research questions.We recruited interdisciplinary experts to identify gaps in the neurotrauma literature, generate research questions, and prioritize those questions using a consensus-driven Delphi survey approach. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the importance of the questions on a 9-point Likert scale. Consensus was defined as 60% or greater of panelists agreeing on the priority category. We then coded research questions using an National Trauma Research Action Plan taxonomy of 118 research concepts, which were consistent across all 11 panels.Twenty-eight neurotrauma experts generated 675 research questions. Of these, 364 (53.9%) reached consensus, and 56 were determined to be high priority (15.4%), 303 were deemed to be medium priority (83.2%), and 5 were low priority (1.4%). The research topics were stratified into three groups-severe traumatic brain injury (TBI), mild TBI (mTBI), and spinal cord injury. The number of high-priority questions for each subtopic was 46 for severe TBI (19.7%), 3 for mTBI (4.3%) and 7 for SCI (11.7%).This Delphi gap analysis of neurotrauma research identified 56 high-priority research questions. There are clear areas of focus for severe TBI, mTBI, and spinal cord injury that will help guide investigators in future neurotrauma research. Funding agencies should consider these gaps when they prioritize future research.Diagnostic Test or Criteria, Level IV.

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Trial Profile

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles.Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Supplementary Table 1 from A Transcriptional Profiling Study of CCAAT/Enhancer Binding Protein Targets Identifies Hepatocyte Nuclear Factor 3β as a Novel Tumor Suppressor in Lung Cancer

We showed previously that CCAAT/enhancer binding protein α (C/EBPα), a tissue-specific transcription factor, is a candidate tumor suppressor in lung cancer. In the present study, we have performed a transcriptional profiling study of C/EBPα target genes using an inducible cell line system. This study led to the identification of hepatocyte nuclear factor 3β (HNF3β), a transcription factor known to play a role in airway differentiation, as a downstream target of C/EBPα. We found down-regulation of HNF3β expression in a large proportion of lung cancer cell lines examined and identified two novel mutants of HNF3β, as well as hypermethylation of the HNF3β promoter. We also developed a tetracycline-inducible cell line model to study the cellular consequences of HNF3β expression. Conditional expression of HNF3β led to significant growth reduction, proliferation arrest, apoptosis, and loss of clonogenic ability, suggesting additionally that HNF3β is a novel tumor suppressor in lung cancer. This is the first study to show genetic abnormalities of lung-specific differentiation pathways in the development of lung cancer.

Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72 transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72 -repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72 -linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophila model of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72 mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases.

The first synthesis of Ebselen was nearly a full century ago, but despite several clinical trials with Ebselen, the therapeutic application of Ebselen is still uncertain. Nevertheless, it has very low toxicity and its broad activity in the modulation of the redox equilibrium indicates that Ebselen can be a multitarget therapeutic agent against human diseases. Here we will review nearly a dozen clinical trials with Ebselen to treat brain ischemia, cardiovascular problems associated with diabetes mellitus, noise-induced hearing loss, and bipolar disorder. The molecular events potentially mediating the effects of Ebselen will be discussed. The approved but still not initiated clinical trials (the studies are in the recruiting phase) to treat moderate and severe COVID-19 are highlighted.

Soil life supports the functioning and biodiversity of terrestrial ecosystems. Springtails (Collembola) are among the most abundant soil arthropods regulating soil fertility and flow of energy through above- and belowground food webs. However, the global distribution of springtail diversity and density, and how these relate to energy fluxes remains unknown. Here, using a global dataset representing 2470 sites, we estimate the total soil springtail biomass at 27.5 megatons carbon, which is threefold higher than wild terrestrial vertebrates, and record peak densities up to 2 million individuals per square meter in the tundra. Despite a 20-fold biomass difference between the tundra and the tropics, springtail energy use (community metabolism) remains similar across the latitudinal gradient, owing to the changes in temperature with latitude. Neither springtail density nor community metabolism is predicted by local species richness, which is high in the tropics, but comparably high in some temperate forests and even tundra. Changes in springtail activity may emerge from latitudinal gradients in temperature, predation and resource limitation in soil communities. Contrasting relationships of biomass, diversity and activity of springtail communities with temperature suggest that climate warming will alter fundamental soil biodiversity metrics in different directions, potentially restructuring terrestrial food webs and affecting soil functioning. The article is an outcome of the #GlobalCollembola community initiative that is voluntarily supported by researchers around the world. Data collection and analysis was supported by the Russian Science Foundation (19-74-00154 to A.P.) and by Deutsche Forschungsgemeinschaft (493345801 to A.P. and 192626868—SFB 990 to S.S.). We acknowledge support by the Open Access Publication Funds of the Göttingen University. The following funding bodies provided support for individual contributors: ARC SRIEAS Grant SR200100005 Securing Antarctica’s Environmental Future to S.L.C., Slovak Scientific Grant Agency VEGA 1/0438/22 to Ľ.K., RFBR 19-516-60002 to N.A.K., Carl Tryggers Stiftelse för Vetenskaplig Forskning and Qatar Petroleum to J.M.A., BIO 27 (2013-2014)-MAGyP and PICTO 2084 (2012)-ANPCyT to V.B., DAAD-19-10 and MSM200962001 to T.C., grant TE, PN-III-P1-1.1-TE-2019-0358 to C.F., NWO grant 821.01.015 to O.F., National Natural Sciences Foundation of China No 41471037 and 41871042 to M.G., BIO 27 (2013-2014), MAGyP; PICT 2084 (2012), FONCyT to D.F.G., NRF South African National Antarctic Programme grant 110734 to M.G., Natural Resources Canada (NRCan), EcoEnergy Innovation Initiative under the Office of Energy Research and Development, and the Natural Sciences and Engineering Research Council of Canada (NSERC) to I.T.H., L.A.V. and L.R., Independent Research Fund Denmark grant no. DFF-4002-00384 to M.H., Estonian Science Foundation G9145 to M.I., SA-France bilateral grant to C.J., SA (NRF)/Russia (RFBR) Joint Science and Technology Research Collaboration project no. 19-516-60002 (FRBR) and no. 118904 (NRF) to M.P. and C.J., European Research Council (ERC), European Union’s Horizon 2020 research and innovation programme (grant agreement no. 677232; to N.E.); iDiv, German Research Foundation (DFG–FZT 118, 202548816) to M.J. and N.E., French National Agency of Research (ANR) (JASSUR research project; ANR-12-VBDU-0011), «Ministère de l’Agriculture et de la Pêche» and «Ministère de l’Education Nationale de la Recherche et de la Technologie» (ACTA programme), «Ministère de l’Aménagement du Territoire et de l’Environnement» (Pnetox programme), EU-funded project, ECOGEN QLK5-CT-2002-01666 (www.ecogen.dk), “Agence de l’Environnement et de la Maîtrise de l'Énergie” (BIOINDICATEUR 2, BIOTECHNOSOL), ANDRA and GISFI (www.gisfi.fr) to S.J., GRR SER-BIODIV (Région Normandie, France) to MCha, ESF9258, B02 to A.K., Fundamental Research Funds for the Central Universities (grant no. 2018CDXYCH0014) to D.L., DFG 316045089 to J.L., Massey University Research Fund grant to M.A.M., DFG SCHE 376/38-2 to M.M.P., grant from the Austria Academy of Science: Heritage_2020-043_Modeling-Museum to P.Q., Slovak Scientific Grant Agency: VEGA Nos. 1/0441/03 and 1/3267/06 to N.R., Higher Education Commission of Pakistan to M.I.R., RSF 21-74-00126 to R.A.S., Austrian Federal Government and European Union (Rural Development 2014-2020) to J.S., АААА-А17-122040600025-2 to A.A.T., Brazilian Council for Scientific and Technological Development—CNPq (grant no. 152717/2016-1) to B.R.W., 309030/2018-8 to D.Z. and 305426/2018-4 to B.C.B., National Natural Science Foundation of China (31970434, 31772491) to N.N.G., Research and Innovation Support Foundation of Santa Catarina (FAPESC) (6.309/2011-6/FAPESC) and the CNPq (563251/2010-7/CNPq) to L.C.I.O.F., O.K.-F., the Latvian Council of Science Grants no. 90.108, 93.140, 96.0110, 01.0344 to E.J., CNPq for the Research Productivity Grant (305939/2018-1) to D.B., FPI-MICINN grant in the project INTERCAPA (CGL2014-56739-R) to P.H, the Natural Sciences and Engineering Research Council of Canada (NSERC) to Z.L., Ministry of Innovation and Technology of Hungary TKP2021-NKTA-43 to D.W. Authors are grateful to Penelope Greenslade for providing the literature on Australian Collembola communities. Authors are grateful to Frans Janssens for providing the global checklist of Collembola.

Background Triatoma guasayana is considered an emerging vector of Chagas disease in the Southern Cone of South America. The presence of a triatomine population with brachypterous individuals, in which both wings are reduced, has recently been reported for this species. The aim of the present study was to determine if flight-related traits varied across populations, if these traits could explain differences in flight capacity across populations and if flight-related traits are associated with geographic and/or climatic variation. Methods The study involved 66 male T. guasayana specimens from 10 triatomine populations. Digital images of wing, head and pronotum were used to estimate linear and geometric morphometric variables. Variations in size and shape were analysed using one-way analysis of variance and canonical variate analysis (CVA), respectively. Mantel tests were applied to analyse the relationship between morphometric and geographic distances, and the association between size measurements was analysed using Pearson’s correlation. We explored covariation between size and shape variables using partial least square analyses (PLS). The association of geographic and climatic variables with size measurements was tested using linear regression analyses. We performed PLS analyses for shape measurements. Results Wing size differed significantly across triatomine populations. The CVA showed that wing shape of the brachypterous population is well discriminated from that of the other populations. The Mantel test showed a positive and significant association between wing shape and geographic distances. The heads of the brachypterous population were significantly larger than those of the other populations. Similar to wing shape, the head shape of the brachypterous population was well discriminated from those of the other populations. Pronotum width did not show significant differences across populations. Geographic and climatic factors were associated with size and shape of both the wing and head, but not with pronotum width. Conclusions Most of the traits related to flight dispersal varied across populations. Wing shape and head shape were found to be better markers for differentiated morphological variation across populations. Head measurements also varied in accordance with this condition. Geographic and climatic variables were associated with most of the flight-related traits. Graphical Abstract

BackgroundHybrids are expected to show greater phenotypic variation than their parental species, yet how hybrid phenotype expression varies with genetic distances in closely-related parental species remains surprisingly understudied. Here we study pelage and morphometric trait variation in anthropogenic hybrids between four species of BrazilianCallithrixmarmosets, a relatively recent primate radiation. Marmoset species are distinguishable by pelage phenotype and level of morphological specialization for eating tree exudates. Here, we (1) describe qualitative phenotypic pelage differences between parental species and hybrids; (2) test whether significant quantitative differences exist between parental and hybrid morphometric phenotypes; and (3) determine which hybrid morphometic traits show heterosis, dysgenesis, trangression, or intermediacy relative to the parental trait. For morphometric traits, we investigated both cranial and post-cranial traits, particularly as most hybrid morphological studies focus on the former instead of the latter. Finally, we estimate mitogenomic distances between marmoset species from previously published data.ResultsHybrid facial and overall body pelage variation reflected coloration and patterns seen in parental species. In morphometric traits,C. jacchusandC. penicillatawere the most similar to each other, whileC. auritawas the most distinct, andC. geoffroyitrait measures fell between these other species. Most traits inC. jacchusxC. penicillatahybrids showed either heterosis or were intermediate relative to the parental trait values. We observed heterosis and dygenesis in traits ofC. penicillataxC. geoffroyihybrids. Trangressive segregation was observed in hybrids ofC. auritaand the other species. These hybrids were alsoC. aurita-like for a number of traits. Genetic distance was closest betweenC. jacchusandC. penicillataand farthest betweenC. auritaand the other species.ConclusionWe attributed significant phenotypic differences between marmoset species to differences in morphological exudivory specialization in these species. Our results suggest that intermediate hybrid traits relative to the parental trait values are more likely in crosses between species with relatively lesser genetic distance. More extreme phenotypic variation is more likely in parental species with greater genetic distance, with transgressive traits appearing in hybrids of the most genetically distant parental species. We further suggest that that less developmental disturbances can be expected in hybrids of more recently diverged parental species.