Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.

Ubiquitous acceleration in Greenland Ice Sheet calving from 1985 to 2022.

Nearly every glacier in Greenland has thinned or retreated over the past few decades1-4, leading to glacier acceleration, increased rates of sea-level rise and climate impacts around the globe5-9. To understand how calving-front retreat has affected the ice-mass balance of Greenland, we combine 236,328 manually derived and AI-derived observations of glacier terminus positions collected from 1985 to 2022 and generate a 120-m-resolution mask defining the ice-sheet extent every month for nearly four decades. Here we show that, since 1985, the Greenland Ice Sheet (GrIS) has lost 5,091 ± 72 km2 of area, corresponding to 1,034 ± 120 Gt of ice lost to retreat. Our results indicate that, by neglecting calving-front retreat, current consensus estimates of ice-sheet mass balance4,9 have underestimated recent mass loss from Greenland by as much as 20%. The mass loss we report has had minimal direct impact on global sea level but is sufficient to affect ocean circulation and the distribution of heat energy around the globe10-12. On seasonal timescales, Greenland loses 193 ± 25 km2 (63 ± 6 Gt) of ice to retreat each year from a maximum extent in May to a minimum between September and October. We find that multidecadal retreat is highly correlated with the magnitude of seasonal advance and retreat of each glacier, meaning that terminus-position variability on seasonal timescales can serve as an indicator of glacier sensitivity to longer-term climate change.

Serine Supports Epithelial and Immune Cell Function in Colitis.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, and mucosal healing is critical for remission. Serine is a nonessential amino acid that supports epithelial and immune cell metabolism and proliferation; however, whether these roles affect IBD pathogenesis is not well understood. Herein, the study showed that serine synthesis increased selectively in the epithelial cells of colons from patients with IBD and murine models of colitis. Inhibiting serine synthesis impaired colonic mucosal healing and increased susceptibility to acute injury in mice, effects associated with diminished epithelial cell proliferation. Dietary removal of serine similarly sensitized mice to acute chemically induced colitis but ameliorated inflammation in chronic colitis models. The anti-inflammatory effect of exogenous serine depletion in chronic colitis was associated with mitochondrial dysfunction of macrophages, resulting in impaired nucleotide production and proliferation. Collectively, these results suggest that serine plays an important role in both epithelial and immune cell biology in the colon and that modulating its availability could impact IBD pathogenesis.

Characterization of integrated Marek's disease virus genomes supports a model of integration by homology-directed recombination and telomere-loop-driven excision.

IMPORTANCE: Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV is only partially controlled by available vaccines, and the virus retains the ability to replicate and spread between vaccinated birds. Following an initial infection, MDV enters a latent state and integrates into host telomeres and this may be a prerequisite for malignant transformation, which is usually fatal. To understand the mechanism that underlies the dynamic relationship between integrated-latent and reactivated MDV, we have characterized integrated MDV (iMDV) genomes and their associated telomeres. This revealed a single orientation among iMDV genomes and the loss of some terminal sequences that is consistent with integration by homology-directed recombination and excision via a telomere-loop-mediated process.

Dispositional mindfulness moderates the links between potentially morally injurious event exposure and symptoms of anxiety and depression but not suicidal ideation.

Exposure to potentially morally injurious events (PMIEs) is a pervasive threat for military service members and may be associated with symptoms of anxiety, depression, and suicidal ideation. However, coping mechanisms, such as mindfulness, may ameliorate symptoms and improve recovery. Two studies were conducted to test dispositional mindfulness as a moderator of the links between PMIEs, as assessed using the Moral Injury Events Scale (i.e., total score and Self-Transgression, Other-Transgression, and Betrayal subscale scores), and symptoms of anxiety, depression, and suicidal ideation among different samples of active-duty soldiers in garrison. In Sample 1 (N = 310), mindfulness buffered the links between PMIE exposure and symptoms of both anxiety, ∆R2 = .02, and depression, ∆R2 = .03. In Sample 2 (N = 669), mindfulness moderated the link between the MIES Betrayal subscale and anxiety symptoms, ∆R2 = .01. The results suggest that dispositional mindfulness may be a protective factor against some of the negative impacts of PMIE exposure. Further implications are discussed.

Cerebral autoregulation-based mean arterial pressure targets and delirium in critically ill adults without brain injury: a retrospective cohort study.

PURPOSE: Cerebral autoregulation (CA) is a mechanism that acts to maintain consistent cerebral perfusion across a range of blood pressures, and impaired CA is associated with delirium. Individualized CA-derived blood pressure targets are poorly characterized in critically ill patients and the association with intensive care unit (ICU) delirium is unknown. Our objectives were to characterize optimal mean arterial pressure (MAPopt) ranges in critically ill adults without brain injury and determine whether deviations from these targets contribute to ICU delirium. METHODS: We performed a retrospective cohort analysis of patients with shock of any etiology and/or respiratory failure requiring invasive mechanical ventilation, without a neurologic admitting diagnosis. Patients were screened daily for delirium. Cerebral oximetry and mean arterial pressure data were captured for the first 24 hr from enrolment. RESULTS: Forty-two patients with invasive blood pressure monitoring data were analyzed. Optimal mean arterial pressure targets ranged from 55 to 100 mm Hg. Optimal mean arterial pressure values were not significantly different based on history of hypertension or delirium status, and delirium was not associated with deviations from MAPopt. Nevertheless, the majority (69%) of blood pressure targets exceeded the current 65 mm Hg Surviving Sepsis guidelines. CONCLUSION: We observed that MAPopt targets across patients were highly variable, but did not observe an association with the incidence of delirium. Studies designed to evaluate the impact on neurologic outcomes are needed to understand the association with individualized mean arterial pressure targets in the ICU. STUDY REGISTRATION: ClinicalTrials.gov (NCT02344043); first submitted 22 January 2015.

RéSUMé: OBJECTIF: L'autorégulation cérébrale (AC) est un mécanisme qui agit pour maintenir une perfusion cérébrale constante pour une gamme de tensions artérielles, et une altération de l'AC est associée au delirium. Les cibles de tension artérielle individualisées dérivées de l'AC sont mal caractérisées chez les patient·es gravement malades et l'association avec le delirium à l'unité de soins intensifs (USI) est inconnue. Nos objectifs étaient de caractériser la tension artérielle moyenne optimale (TAMopt) chez les adultes gravement malades sans lésion cérébrale et de déterminer si les écarts par rapport à ces cibles contribuaient au delirium à l'USI. MéTHODE: Nous avons réalisé une analyse de cohorte rétrospective de patient·es présentant un choc de toute étiologie et/ou une insuffisance respiratoire nécessitant une ventilation mécanique invasive, et n'ayant pas reçu de diagnostic d'atteinte neurologique à l'admission. Les patients ont été dépistés quotidiennement pour le delirium. Les données d'oxymétrie cérébrale et de tension artérielle moyenne ont été saisies pendant les 24 premières heures suivant le recrutement. RéSULTATS: Quarante-deux patient·es pour qui des données de monitorage invasif de la tension artérielle étaient disponibles ont été analysé·es. Les cibles optimales de tension artérielle moyenne variaient de 55 à 100 mm Hg. Les valeurs optimales de tension artérielle moyenne n'étaient pas significativement différentes en fonction des antécédents d'hypertension ou de delirium, et le delirium n'était pas associé à des écarts par rapport à la TAMopt. Néanmoins, la majorité (69 %) des cibles de tension artérielle dépassaient celle de 65 mm Hg préconisée par les lignes directrices Surviving Sepsis. CONCLUSION: Nous avons observé que les cibles de TAMopt étaient très variables chez les patient·es, mais nous n'avons pas observé d'association avec l'incidence de delirium. Des études conçues pour évaluer l'impact sur les issues neurologiques sont nécessaires pour comprendre l'association avec les cibles de tension artérielle moyenne individualisées à l'USI. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02344043); soumis pour la première fois le 22 janvier 2015.

Ocean melting of the Zachariae Isstrøm and Nioghalvfjerdsfjorden glaciers, northeast Greenland.

Zachariae Isstrøm (ZI) and Nioghalvfjerdsfjorden (79N) are marine-terminating glaciers in northeast Greenland that hold an ice volume equivalent to a 1.1-m global sea level rise. ZI lost its floating ice shelf, sped up, retreated at 650 m/y, and experienced a 5-gigaton/y mass loss. Glacier 79N has been more stable despite its exposure to the same climate forcing. We analyze the impact of ocean thermal forcing on the glaciers. A three-dimensional inversion of airborne gravity data reveals an 800-m-deep, broad channel that allows subsurface, warm, Atlantic Intermediate Water (AIW) (+1.[Formula: see text]C) to reach the front of ZI via two sills at 350-m depth. Subsurface ocean temperature in that channel has warmed by 1.3[Formula: see text]C since 1979. Using an ocean model, we calculate a rate of ice removal at the grounding line by the ocean that increased from 108 m/y to 185 m/y in 1979-2019. Observed ice thinning caused a retreat of its flotation line to increase from 105 m/y to 217 m/y, for a combined grounding line retreat of 13 km in 41 y that matches independent observations within 14%. In contrast, the limited access of AIW to 79N via a narrower passage yields lower grounded ice removal (53 m/y to 99 m/y) and thinning-induced retreat (27 m/y to 50 m/y) for a combined retreat of 4.4 km, also within 12% of observations. Ocean-induced removal of ice at the grounding line, modulated by bathymetric barriers, is therefore a main driver of ice sheet retreat, but it is not incorporated in most ice sheet models.

Oral cinacalcet administration decreases serum ionized calcium and parathyroid hormone concentrations in healthy dogs.

Cinacalcet is an oral calcimimetic that has potential to non-invasively treat primary hyperparathyroidism in dogs (Canis lupis familiaris). There is minimal data assessing its efficacy in dogs. This study aimed to determine whether a single dose of cinacalcet decreases serum ionized calcium (iCa), total calcium (tCa), and parathyroid hormone (PTH) concentrations. Twelve dogs received a median dose of 0.49 mg/kg (range 0.30-0.69 mg/kg) cinacalcet per os. Venous blood samples were collected at time 0 (before cinacalcet administration), 3, 8, and 24 h following cinacalcet administration. PTH, iCa, and tCa concentrations were measured at each time point and compared to 0 hour concentrations. A significant (50%) decrease in serum PTH occurred at 3 h with a median PTH of 4.6 pmol/L (range 2.7-10.8) at baseline and 1.65 pmol/L (range 0.5-14.7) at 3 h; p = .005. A significant, but not clinically relevant, decrease in serum iCa from a median baseline of 1.340 mmol/L (range 1.32-1.41) to a 3 h median of 1.325 mmol/L (range 1.26-1.39), p = .043, was also observed. tCa concentrations were not different. This study showed that a single dose of cinacalcet leads to transient decreases in iCa and PTH concentrations in healthy dogs.

Urine Contamination Prevalence Using a Midstream Collection Device Compared with Clean Voided Collections in Dogs.

Collecting clean-caught voided urine samples is minimally invasive, but contamination occurs when urine passes through the nonsterile urethra and external genitalia. Discarding the initial urine stream may reduce these contaminants. This study hypothesized that using a midstream urine collection device would decrease bacterial and cellular contamination as compared with cleanly caught voided urine. This descriptive cross-sectional study collected urine from dogs using standard clean-caught (SCC), midstream collection device (MCD), and cystocentesis (CYS) techniques. Urinalysis and aerobic urine culture characteristics were recorded with each characteristic's prevalence described using percentages and 95% confidence intervals for each mode of collection. Positive urine culture prevalence did not differ between SCC and MCD (adjusted P value = .099); however, CYS had a lower prevalence compared with SCC and MCD (adjusted P values of <.001 [CYS versus SCC] and 0.009 [CYS versus MCD]). For other variables, there was no difference in prevalence when comparing SCC with MCD. There was no identified advantage to collecting urine using an MCD as compared with the SCC technique. Either option is a suitable alternative when CYS is not practical; however, clinicians need to interpret results cautiously because bacterial contamination is more common as compared with CYS.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-ß pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-ß pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-ß pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Association of program-specific variation in bariatric surgery volume for Medicaid patients and access to care: a tale of inequality?

BACKGROUND: Although patients with lower socioeconomic status are at higher risk of obesity, bariatric surgery utilization among patients with Medicaid is low and may be due to program-specific variation in access. Our goal was to compare bariatric surgery programs by percentage of Medicaid cases and to determine if variation in distribution of patients with Medicaid could be linked to adverse outcomes. METHODS: Using a state-wide bariatric-specific data registry that included 43 programs performing 97,207 cases between 2006 and 2020, we identified all patients with Medicaid insurance (n = 4780, 4.9%). Bariatric surgery programs were stratified into quartiles according to the percentage of Medicaid cases performed and we compared program-specific characteristics as well as baseline patient characteristics, risk-adjusted complication rates and wait times between top and bottom quartiles. RESULTS: Program-specific distribution of Medicaid cases varied between 0.69 and 22.4%. Programs in the top quartile (n = 11) performed 18,885 cases in total, with a mean of 13% for Medicaid patients, while programs in the bottom quartile (n = 11) performed 32,447 cases in total, with a mean of 1%. Patients undergoing surgery at programs in the top quartile were more likely to be Black (20.2% vs 13.5%, p < 0.0001), have diabetes (35.1% vs 29.5%, p < 0.0001), hypertension (55.1% vs 49.6%, p < 0.0001) and hyperlipidemia (47.6% vs 45.2%, p < 0.0001). Top quartile programs also had higher complication rates (8.4% vs 6.6%, p < 0.0001), extended length of stay (5.6% vs 4.0%, p < 0.0001), Emergency Department visits (8.1% vs 6.5%, p < 0.0001) and readmissions (4.7% vs 3.9%, p < 0.0001). Median time from initial evaluation to surgery date was also significantly longer among top quartile programs (200 vs 122 days, p < 0.0001). CONCLUSIONS: Bariatric surgery programs that perform a higher proportion of Medicaid cases tend to care for patients with greater disease severity who experience delays in care and also require more resource utilization. Improving bariatric surgery utilization among patients with lower socioeconomic status may benefit from insurance standardization and program-centered incentives to improve access and equitable distribution of care.

Modelling sound particle motion in shallow watera).

Fish species and aquatic invertebrates are sensitive to underwater sound particle motion. Studies on the impact of sound on marine life would benefit from sound particle motion models. Benchmark cases and solutions are proposed for the selection and verification of appropriate models. These include a range-independent environment, with and without shear in the sediment, and a range-dependent environment, without sediment shear. Analysis of the acoustic impedance illustrates that sound particle velocity can be directly estimated from the sound pressure field in shallow water scenarios, except at distances within one wavelength of the source, or a few water depths at frequencies where the wavelength exceeds the water depth.

Risk factors of enterococcal bacteriuria in cats: A retrospective study.

Objective: To determine if factors associated with urothelial damage and inflammation, including urinary catheterization, urinary obstruction, and urolithiasis are associated with the presence of enterococcal bacteriuria in cats. Animals: Thirty-one cats with Enterococcus spp. bacteriuria and 31 cats with Escherichia coli bacteriuria. Procedure: A retrospective case-control study with cases and controls identified by records search for Enterococcus spp. (case) and E. coli (control) bacteriuria from August 1, 2014 to July 31, 2019. Cases and controls were balanced with respect to average age. Binary logistic regression was used to estimate and test whether the odds of having Enterococcus spp. bacteriuria (instead of E. coli) were associated with the presence of any characteristic. Results: Urinary catheterization, urinary obstruction, and urolithiasis were not observed more often in Enterococcus cases versus E. coli controls (19% versus 25%, P = 0.543; 19% versus 32%, P = 0.244; and 16% versus 16%, P = 1, respectively). Signs of lower urinary tract disease were significantly less common in Enterococcus cases than in E. coli controls (OR: 0.30; 95% CI: 0.10 to 0.83, P = 0.02). Hematuria was significantly less common in cases than controls (P = 0.048). Conclusion: No association was identified between urinary catheterization, urolithiasis, or any other comorbidities (hyperthyroidism, chronic kidney disease) and enterococcal bacteriuria in cats. Clinical relevance: Unlike in humans and dogs, urothelial damage and inflammation caused by factors such as urinary catheterization and urolithiasis may not be the mechanism for enterococcal bacteriuria in cats.

Facteurs de risque de bactériurie à entérocoque chez le chat : une étude rétrospective. Objectif: Déterminer si les facteurs associés aux lésions et à l'inflammation urothéliales, y compris le cathétérisme urinaire, l'obstruction urinaire et les lithiases urinaires, sont associés à la présence de bactériurie à entérocoque chez le chat. Animaux: Trente et un chats avec bactériurie à Enterococcus spp. et 31 chats atteints de bactériurie à Escherichia coli. Procédure: Une étude cas-témoins rétrospective avec des cas et des témoins identifiés par la recherche de dossiers pour bactériurie à Enterococcus spp. (cas) et à E. coli (témoin) du 1er août 2014 au 31 juillet 2019. Les cas et les témoins étaient équilibrés par rapport à l'âge moyen. La régression logistique binaire a été utilisée pour estimer et tester si la probabilité d'avoir une bactériurie à Enterococcus spp. (au lieu d'E. coli) était associée à la présence de n'importe quelle caractéristique. Résultats: Le cathétérisme urinaire, l'obstruction urinaire et la lithiase urinaire n'ont pas été observés plus souvent chez les cas avec Enterococcus spp. par rapport aux témoins avec E. coli (19 % vs 25 %, P = 0,543; 19 % vs 32 %, P = 0,244; et 16 % vs 16 %, P = 1, respectivement). Les signes de maladie des voies urinaires inférieures étaient significativement moins fréquents chez les cas à Enterococcus que chez les témoins à E. coli (OR : 0,30; IC à 95 % : 0,10 à 0,83, P = 0,02). L'hématurie était significativement moins fréquente chez les cas que chez les témoins (P = 0,048). Conclusion: Aucune association n'a été identifiée entre le cathétérisme urinaire, la lithiase urinaire ou toute autre comorbidité (hyperthyroïdie, maladie rénale chronique) et la bactériurie à entérocoque chez le chat. Pertinence clinique: Contrairement aux humains et aux chiens, les lésions urothéliales et l'inflammation causées par des facteurs tels que le cathétérisme urinaire et la lithiase urinaire peuvent ne pas être le mécanisme pour la bactériurie à entérocoque chez les chats.(Traduit par Dr Serge Messier).

Limitations of benefit finding as a coping mechanism for combat-related PTSD symptoms.

Benefit finding has been identified as a buffer of the combat exposure-PTSD symptom link in soldiers. However, benefit finding may have a limited buffering capacity on the combat-PTSD symptom link over the course of a soldier's post-deployment recovery period. In the present study, soldiers returning from Operation Iraqi Freedom (OIF) were surveyed at two different time periods post-deployment: Time 1 was 4 months post-deployment (n = 1,510), and Time 2 was at 9 months post-deployment (n = 783). The surveys assessed benefit finding, PTSD symptoms, and combat exposure. Benefit finding was a successful buffer of the cross-sectional relationship between combat exposure and PTSD reexperiencing symptoms at Time 1, but not at Time 2. In addition, the benefit finding by combat interaction at time 1 revealed that greater benefit finding was associated with higher symptoms under high combat exposure at Time 2 after controlling for PTSD arousal symptoms at Time 1. The results of the present study indicate that benefit finding may have a buffering capacity in the immediate months following a combat deployment, but also indicates that more time than is allotted during the post-deployment adjustment period is needed to enable recovery from PTSD. Theoretical implications are discussed.

Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.

Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice. PIDO expressing murine islets maintain robust dynamic insulin secretion in vitro and when transplanted in allogeneic hyperglycemic murine recipients reverse pre-existing streptozotocin-induced and autoimmune diabetes in the absence of pharmacological immunosuppression for more than 50 and 8 weeks, respectively, and is dependent on host CD4 competence. Additionally, PIDO expression in allografts preserves endocrine functional viability of islets and promotes a localized tolerogenic milieu characterized by the suppression of host CD8 T cell and phagocyte recruitment and accumulation of FOXP3+ Tregs. Furthermore, in the canine model of xenogeneic islet transplantation, muscle implanted PIDO-expressing porcine islets displayed physiological glucose-responsive insulin secretion competency in euglycemic recipient for up to 20 weeks. In conclusion, the PIDO transgenic technology enables host CD4+ T cell-modulated immune evasiveness and long-term functional viability of islet allo- and xenografts in immune-competent recipients without the need for pharmacological immune suppression and would allow for improved outcomes for tissue transplantation.

Strategic roadmap to assess forest vulnerability under air pollution and climate change.

Although it is an integral part of global change, most of the research addressing the effects of climate change on forests have overlooked the role of environmental pollution. Similarly, most studies investigating the effects of air pollutants on forests have generally neglected the impacts of climate change. We review the current knowledge on combined air pollution and climate change effects on global forest ecosystems and identify several key research priorities as a roadmap for the future. Specifically, we recommend (1) the establishment of much denser array of monitoring sites, particularly in the South Hemisphere; (2) further integration of ground and satellite monitoring; (3) generation of flux-based standards and critical levels taking into account the sensitivity of dominant forest tree species; (4) long-term monitoring of N, S, P cycles and base cations deposition together at global scale; (5) intensification of experimental studies, addressing the combined effects of different abiotic factors on forests by assuring a better representation of taxonomic and functional diversity across the ~73,000 tree species on Earth; (6) more experimental focus on phenomics and genomics; (7) improved knowledge on key processes regulating the dynamics of radionuclides in forest systems; and (8) development of models integrating air pollution and climate change data from long-term monitoring programs.

Some observations on meaningful and objective inference in radioecological field studies.

Anthropogenic releases of radiation are of ongoing importance for environmental protection, but the radiation doses at which natural systems begin to show effects are controversial. More certainty is required in this area to achieve optimal regulation for radioactive substances. We recently carried out a large survey (268 sampled animals and 20 sites) of the association between environmental radiation exposures and small mammal gut-associated microbiomes (fungal and bacterial) in the Chornobyl Exclusion zone (CEZ). Using individual measurements of total absorbed dose rates and a study design and analyses that accounted for spatial non-independence, we found no, or only limited, association. Watts et al. have criticised our study: for not filtering candidate non-resident components prior to our fungal microbiome analyses, for our qualified speculations on the relative merits of faecal and gut samples, and for the design of our study which they felt lacked sufficient replication. The advantage of filtering non-resident-fungal taxa is not clear and it would not have changed the null (spatially adjusted) association we found between radioactive dose and mycobiome composition because the most discriminatory fungal taxa with regard to dose were non-resident taxa. We maintain that it was legitimate for us to make qualified discussion comments on the differences in results between our faecal and gut microbiome analyses and on the relative merits of these sample types. Most importantly, the criticism of our study design by Watts et al. and the designs and analysis of their recent studies in the CEZ show a misunderstanding of the true nature of independent replication in field studies. Recognising the importance of spatial non-independence is essential in the design and analysis of radioecological field surveys.

The Use of Near-Infrared Spectroscopy and/or Transcranial Doppler as Non-Invasive Markers of Cerebral Perfusion in Adult Sepsis Patients With Delirium: A Systematic Review.

BACKGROUND: Several studies have previously reported the presence of altered cerebral perfusion during sepsis. However, the role of non-invasive neuromonitoring, and the impact of altered cerebral perfusion, in sepsis patients with delirium remains unclear. METHODS: We performed a systematic review of studies that used near-infrared spectroscopy (NIRS) and/or transcranial Doppler (TCD) to assess adults (≥18 years) with sepsis and delirium. From study inception to July 28, 2020, we searched the following databases: Ovid MedLine, Embase, Cochrane Library, and Web of Science. RESULTS: Of 1546 articles identified, 10 met our inclusion criteria. Although NIRS-derived regional cerebral oxygenation was consistently lower, this difference was only statistically significant in one study. TCD-derived cerebral blood flow velocity was inconsistent across studies. Importantly, both impaired cerebral autoregulation during sepsis and increased cerebrovascular resistance were associated with delirium during sepsis. However, the heterogeneity in NIRS and TCD devices, duration of recording (from 10 seconds to 72 hours), and delirium assessment methods (e.g., electronic medical records, confusion assessment method for the intensive care unit), precluded meta-analysis. CONCLUSION: The available literature demonstrates that cerebral perfusion disturbances may be associated with delirium in sepsis. However, future investigations will require consistent definitions of delirium, delirium assessment training, harmonized NIRS and TCD assessments (e.g., consistent measurement site and length of recording), as well as the quantification of secondary and tertiary variables (i.e., Cox, Mxa, MAPOPT), in order to fully assess the relationship between cerebral perfusion and delirium in patients with sepsis.

Forty-six years of Greenland Ice Sheet mass balance from 1972 to 2018.

We reconstruct the mass balance of the Greenland Ice Sheet using a comprehensive survey of thickness, surface elevation, velocity, and surface mass balance (SMB) of 260 glaciers from 1972 to 2018. We calculate mass discharge, D, into the ocean directly for 107 glaciers (85% of D) and indirectly for 110 glaciers (15%) using velocity-scaled reference fluxes. The decadal mass balance switched from a mass gain of +47 ± 21 Gt/y in 1972-1980 to a loss of 51 ± 17 Gt/y in 1980-1990. The mass loss increased from 41 ± 17 Gt/y in 1990-2000, to 187 ± 17 Gt/y in 2000-2010, to 286 ± 20 Gt/y in 2010-2018, or sixfold since the 1980s, or 80 ± 6 Gt/y per decade, on average. The acceleration in mass loss switched from positive in 2000-2010 to negative in 2010-2018 due to a series of cold summers, which illustrates the difficulty of extrapolating short records into longer-term trends. Cumulated since 1972, the largest contributions to global sea level rise are from northwest (4.4 ± 0.2 mm), southeast (3.0 ± 0.3 mm), and central west (2.0 ± 0.2 mm) Greenland, with a total 13.7 ± 1.1 mm for the ice sheet. The mass loss is controlled at 66 ± 8% by glacier dynamics (9.1 mm) and 34 ± 8% by SMB (4.6 mm). Even in years of high SMB, enhanced glacier discharge has remained sufficiently high above equilibrium to maintain an annual mass loss every year since 1998.