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We describe the correction procedure for Analog-to-Digital Converter (ADC) differential non-linearities (DNL) adopted in the Bayesian end-to-end BEYONDPLANCK analysis framework. This method is nearly identical to that developed for the official Planck Low Frequency Instrument (LFI) Data Processing Center (DPC) analysis, and relies on the binned rms noise profile of each detector data stream. However, rather than building the correction profile directly from the raw rms profile, we first fit a Gaussian to each significant ADC-induced rms decrement, and then derive the corresponding correction model from this smooth model. The main advantage of this approach is that only samples which are significantly affected by ADC DNLs are corrected, as opposed to the DPC approach in which the correction is applied to all samples, filtering out signals not associated with ADC DNLs. The new corrections are only applied to data for which there is a clear detection of the non-linearities, and for which they perform at least comparably with the DPC corrections. Out of a total of 88 LFI data streams (sky and reference load for each of the 44 detectors) we apply the new minimal ADC corrections in 25 cases, and maintain the DPC corrections in 8 cases. All these corrections are applied to 44 or 70 GHz channels, while, as in previous analyses, none of the 30 GHz ADCs show significant evidence of non-linearity. By comparing the BEYONDPLANCK and DPC ADC correction methods, we estimate that the residual ADC uncertainty is about two orders of magnitude below the total noise of both the 44 and 70 GHz channels, and their impact on current cosmological parameter estimation is small. However, we also show that non-idealities in the ADC corrections can generate sharp stripes in the final frequency maps, and these could be important for future joint analyses with the Planck High Frequency Instrument (HFI), Wilkinson Microwave Anisotropy Probe (WMAP), or other datasets. We therefore conclude that, although the existing corrections are adequate for LFI-based cosmological parameter analysis, further work on LFI ADC corrections is still warranted.

Fishing catch is often used as a cost in marine conservation planning to avoid areas of high fishing activity when identifying potential marine reserve locations. However, the theory of marine reserves indicates that reserves are more likely to benefit fisheries in areas of heavy fishing activity that would otherwise be overfished. Whether or not fishing catch is calculated as a cost depends on the balance of conservation and fisheries goals for a reserve, and thus is critical for policymakers to consider when designing marine reserve networks. This research shows the utility of running an inverted cost model of fishery catches during marine reserve spatial prioritization as a first step in a marine planning process oriented towards stabilizing local fisheries. This technique serves as a heuristic tool that may help conservation planners explore regions that would otherwise be overlooked if fisheries data were absent or integrated purely as a cost in the planning process. Drawing on data from Madagascar to illustrate our approach, this research demonstrates that the regions most frequently selected using the inverted cost model not only meet conservation targets, but are also those most accessible to community-based resource managers, the dominant management paradigm in Madagascar as well as in many developing countries.

The effects of increasing dietary inclusion levels of L-carnitine at 0 (control group) 200, 400, 600, 1200, 1400, and 1600 mg/kg were evaluated in juvenile hybrid groupers exposed to heat shock stress. The feeding trial was conducted for eight weeks. After the feeding trial, hybrid groupers were subjected to a heat stress test for an hour at a temperature of 36 °C to determine the influence of the treatments on survival, biochemical parameters, and gene expression. The results of the current study showed that the survival rate of hybrid grouper was low in fish fed the control diet. A large number of survivors were observed in the treatment group with 400 mg/kg L-carnitine supplementation (LC 400), obtaining the highest survival rate. Heat stress decreased (P

This research was conducted to assess the effects of replacing fishmeal (FM) with dried distillers grains with solubles (DDGS) at various levels (D0 (0 %), D2 (2 %), D4 (4 %), D6 (6 %), D8 (8 %), D12 (12 %), and D16 (16 %)) on the growth, proximate body composition, serum biochemical indices, antioxidant activities, histology, and disease resistance in juvenile Pacific whiteleg shrimp. Forty shrimp per tank were stocked in seven different tanks with three replicates of each treatment group with an initial weight of 0.23 ± 0.00 g. Their respective experimental diets were used to feed shrimp for 56 days. The results showed an enhancement in shrimp fed dietary DDGS (D8) diets on the growth performance, including final weight, weight gain, acid phosphatase, alkaline phosphatase, glucose, and total antioxidant capacity in the serum (P < 0.05). Decreased FCR and High-Density Lipoprotein Cholesterol were observed in shrimp fed DDGS (D8) diets in serum compared to D0. No severe changes and significant differences in villus height and intestinal wall thickness were observed in the shrimp hepatopancreas and mid-gut among treatment groups. Furthermore, disease resistance increased in shrimp fed the DDGS diet, with D8 obtaining the lowest mortality rate, 50.9 %, compared to the control group (D0), 68.3 %. In summary, regarding all the factors, replacing FM with DDGS at D8 (8 %) in the shrimp diet could modulate and cater to overall growth performance, health and immunity, histology and disease resistance in shrimp.

Abstract Human skin, in common with other organs, ages as a consequence of the passage of time, but in areas exposed to solar ultraviolet radiation, the effects of this intrinsic ageing process are exacerbated. In particular, both the severity and speed of onset of age-related changes, such as wrinkle formation and loss of elasticity, are enhanced in photoaged (also termed extrinsically aged) as compared with aged, photoprotected, skin. The anatomy of skin is characterised by two major layers: an outer, avascular, yet highly cellular and dynamic epidermis and an underlying vascularised, comparatively static and cell-poor, dermis. The structural consequences of photoageing are mainly evident in the extracellular matrix-rich but cell-poor dermis where key extracellular matrix proteins are particularly susceptible to photodamage. Most investigations to date have concentrated on the cell as both a target for and mediator of, ultraviolet radiation-induced photoageing. As the main effectors of dermal remodelling produced by cells (extracellular proteases) generally have low substrate specificity, we recently suggested that the differential susceptibility of key extracellular matrix proteins to the processes of photoageing may be due to direct, as opposed to cell-mediated, photodamage. In this review, we discuss the experimental evidence for ultraviolet radiation (and related reactive oxygen species)-mediated differential degradation of normally long lived dermal proteins including the fibrillar collagens, elastic fibre components, glycoproteins and proteoglycans. Whilst these components exhibit highly diverse primary and hence macro- and supra-molecular structures, we present evidence that amino acid composition alone may be a useful predictor of age-related protein degradation in both photoexposed and, as a consequence of differential oxidation sensitivity, photoprotected, tissues.

We aimed to examine associations between serum 25-hydroxyvitamin D (25[OH]D) concentration and mortality from heart failure (HF) and cardiovascular disease (CVD) and premature death from all causes using data from the Third National Health and Nutrition Examination Survey, which included 13,131 participants (6,130 men, 7,001 women) ≥35 years old at baseline (1988 to 1994) and followed through December 2000. Premature death was defined all-cause death at <75 years of age. Results indicated that during an average 8-year follow-up, there were 3,266 deaths (24.9%) including 101 deaths from HF, 1,451 from CVD, and 1,066 premature all-cause deaths. Among HF deaths, 37% of decedents had serum 25(OH)D levels <20 ng/ml, whereas only 26% of those with non-HF deaths had such levels (p <0.001). Multivariate-adjusted Cox model indicated that subjects with serum 25(OH)D levels <20 ng/ml had 2.06 times higher risk (95% confidence interval 1.01 to 4.25) of HF death than those with serum 25(OH)D levels ≥30 ng/ml (p <0.001). In addition, hazard ratios (95% confidence intervals) for premature death from all causes were 1.40 (1.17 to 1.68) in subjects with serum 25(OH)D levels <20 ng/ml and 1.11 (0.93 to 1.33) in those with serum 25(OH)D levels of 20 to 29 ng/ml compared to those with serum 25(OH)D levels ≥30 ng/ml (p <0.001, test for trend). In conclusion, adults with inadequate serum 25(OH)D levels have significantly higher risk of death from HF and all CVDs and all-cause premature death. [ABSTRACT FROM AUTHOR]

Evolution by natural selection is believed to be the only possible source of spontaneous adaptive organisation in the natural world. This places strict limits on the kinds of systems that can exhibit adaptation spontaneously, i.e., without design. Physical systems can show some properties relevant to adaptation without natural selection or design. (1) The relaxation, or local energy minimisation, of a physical system constitutes a natural form of optimisation insomuch as it finds locally optimal solutions to the frustrated forces acting on it or between its components. (2) When internal structure 'gives way' or accommodates a pattern of forcing on a system, this constitutes learning insomuch, as it can store, recall, and generalise past configurations. Both these effects are quite natural and general, but in themselves insufficient to constitute non-trivial adaptation. However, here we show that the recurrent interaction of physical optimisation and physical learning together results in significant spontaneous adaptive organisation. We call this adaptation by natural induction. The effect occurs in dynamical systems described by a network of viscoelastic connections subject to occasional disturbances. When the internal structure of such a system accommodates slowly across many disturbances and relaxations, it spontaneously learns to preferentially visit solutions of increasingly greater quality (exceptionally low energy). We show that adaptation by natural induction thus produces network organisations that improve problem-solving competency with experience (without supervised training or system-level reward). We note that the conditions for adaptation by natural induction, and its adaptive competency, are different from those of natural selection. We therefore suggest that natural selection is not the only possible source of spontaneous adaptive organisation in the natural world.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination., Competing Interests: Competing interests: RAW, WY, CAT, EJ, RC, OT, TJ, BS, MH, DJ, RP, EI, SJ, DM-P, NC and MP: no competing interests. MRM reports grants from Roche, grants from Astrazeneca, grants from GSK, other from Novartis, grants and other from Immunocore, other from BMS, other from Pfizer, other from Merck/MSD, other from Regeneron, other from BiolineRx, other from Replimune, grants from GRAIL; all outside the submitted work; ISDR reports consultancy for Novartis, Travere Therapeutics, Q32Bio and is an unpaid Director of Oxford Pathology Education Limited, Oramis Digital Autopsy, UK Renal Pathology; all outside submitted work. BF has received speaker fees from GSK, Immunocore, BMS and reports consultancy for Roche, Pathios Therapeutics, NICE advisory, UCB; NC has received honoraria Pierre Fabre, BMS., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

A new database on historical country-level fishing fleet capacity and effort is described, derived from a range of publicly available sources that were harmonized, converted to fishing effort, and mapped to 30-min spatial cells. The resulting data is comparable with widely used but more temporally-limited satellite-sourced Automatic Identification System (AIS) datasets for large vessels, while also documenting important smaller fleets and artisanal segments. It ranges from 1950 to 2017, and includes information on number of vessels, engine power, gross tonnage, and nominal effort, categorized by vessel length, gear type and targeted functional groups. The data can be aggregated to Large Marine Ecosystem, region and/or fishing country scales and provides a temporally and spatially explicit source for fishing effort and fleet capacity for studies aimed at understanding the implications of long-term changes in fishing activity in the global ocean., (© 2024. The Author(s).)

Objectives: The use of bioprosthetic aortic valve replacement (AVR) is inherently associated with a risk of structural valve degeneration (SVD) and the need for aortic valve (AV) reintervention. We sought to evaluate whether AV reintervention, in the form of repeat surgical AVR (SAVR) or valve-in-valve transcatheter aortic valve replacement (ViV-TAVR), negatively affects patients' subsequent long-term survival after index SAVR., Methods: We identified patients who had undergone bioprosthetic SAVR from 2002 to 2017 at our institution. Median longitudinal follow-up after index SAVR was 7.3 years (10.9 years for those with and 7.2 years for those without AV reintervention), and median follow-up after AV reintervention was 1.9 years. Cox regression analyses using AV reintervention (re-SAVR and ViV-TAVR) as a time-varying covariate were used to determine the impact of reintervention on subsequent survival., Results: Of 4167 patients who underwent index SAVR, 139 (3.3%) required AV reintervention for SVD, with re-SAVR being performed in 65 and ViV-TAVR in 74. Median age at the index SAVR was 73 years (interquartile range, 64-79 years), and 2541 (61%) were male. Overall, there were total of 1171 mortalities observed, of which 13 occurred after re-SAVR and 9 after ViV-TAVR. AV reintervention was associated with a greater risk of subsequent mortality compared with those patients who did not require AV reintervention (hazard ratio, 2.53; 95% confidence interval, 1.64-3.88, P  < .001). This increased risk of subsequent mortality was more pronounced for those who received their index AVR when <65 years of age (hazard ratio, 5.60; 95% confidence interval, 2.57-12.22, P  < .001) versus those ≥65 years (2.06, 1.21-3.52, P  = .008). Direct comparison of survival between those who underwent re-SAVR versus ViV-TAVR showed 5-year survival to be comparable (re-SAVR: 74% vs ViV-TAVR: 80%, P  = .67)., Conclusions: Among patients receiving bioprosthetic AVR, an AV reintervention for SVD is associated with an increased risk of subsequent mortality, regardless of re-SAVR or ViV-TAVR, and this risk is greater among younger patients. These findings should be balanced with individual preferences at index AVR in the context of patients' lifetime management of aortic stenosis., Competing Interests: Dr Kaneko is a consultant for Edwards Life Sciences, Medtronic, 4C Medical, Abbott, and Baylis. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Punctuated bursts of structural genomic variations (SVs) have been described in various organisms, but their etiology remains incompletely understood. Homologous recombination (HR) is a template-guided mechanism of repair of DNA double-strand breaks and stalled or collapsed replication forks. We recently identified a DNA break amplification and genome rearrangement pathway originating from the endonucleolytic processing of a multi-invasion (MI) DNA joint molecule formed during HR. Genome-wide approaches confirmed that multi-invasion-induced rearrangement (MIR) frequently leads to several repeat-mediated SVs and aneuploidies. Using molecular and genetic analysis and a novel, highly sensitive proximity ligation-based assay for chromosomal rearrangement quantification, we further delineate two MIR subpathways. MIR1 is a universal pathway occurring in any sequence context, which generates secondary breaks and frequently leads to additional SVs. MIR2 occurs only if recombining donors exhibit substantial homology and results in sequence insertion without additional breaks or SVs. The most detrimental MIR1 pathway occurs late on a subset of persisting DNA joint molecules in a PCNA/Pol δ -independent manner, unlike recombinational DNA synthesis. This work provides a refined mechanistic understanding of these HR-based SV formation pathways and shows that complex repeat-mediated SVs can occur without displacement DNA synthesis. Sequence signatures for inferring MIR1 from long-read data are proposed., (© 2023 Reitz et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Mifepristone, also known as RU-486, is an anti-progestational steroid with similar chemical structure to anabolic steroids. Given as a single dose in conjunction with misoprostol, mifepristone is used to induce medical abortion. Mifepristone administered chronically at a higher dose is also approved for the management of hypercortisolism. There have been only 2 reported cases of mifepristone associated liver injury, in both cases, in the setting of Cushing syndrome. We report a third patient with Cushing syndrome with mifepristone induced liver injury with unique histological findings that provide insight to the pathophysiology of liver injury in mifepristone and anabolic steroids., Case Presentation: Patient is a 63-year-old Caucasian female Cushing disease with no prior history of liver disease. She was started on mifepristone and semaglutide. Ninety days after initiating mifepristone, she developed deep jaundice, severe pruritus, fatigue, and nausea. Liver tests revealed a mixed hepatocellular/cholestatic pattern. Viral and autoimmune serologies were negative and there was no biliary dilatation on imaging. Liver biopsy showed severe cholestasis but no bile duct injury. Focal endothelialitis was present within a central venule. Cholestatic symptoms persisted for one month after presentation before slowly subsiding. Four months after stopping mifepristone, the patient's symptoms completely resolved, and liver tests became normal. Compilation of Roussell Uclaf Causality Assessment Method score indicated probable causality., Conclusions: Mifepristone shares a similar chemical structure as synthetic anabolic/androgenic steroids and there are many similarities in the clinical presentation of liver injury. This case and the 2 other reported cases share similar clinical characteristics. The observation of endothelialitis in our patient may provide a mechanistic link between mifepristone, or anabolic steroids in general, and the development of vascular complications such as peliosis., (© 2023. The Author(s).)

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies., (© 2023. The Author(s).)

For decades, the potential role of probiotics in the prevention and treatment of recurrent urinary tract infections has been extensively studied. However, achieving an effective problem-solving strategy has thus far proven elusive. Perhaps adopting a military paradigm might expedite our assault on chronic, recurring bacteriuria in women. What is needed is a targeted strategy with specific attention to (1) the enemy: the case-specific uropathogen; (2) the battlefield: the extraordinarily complex interplay of factors within the bladder, unique to a given patient, which interface with profoundly important influences from the gut biome, as well as the vaginal biota; (3) the weapon: an antimicrobial probiotic with demonstrated activity against that specific uropathogen; (4) a new strategy: taking these complexities into account, we posit a key role for the instillation of case-specific lactobacilli directly into the bladder of the designated patient. This newly proposed, targeted intervention might be termed "Probiotic Intravesical Organic Therapy-PIVOT"; and (5) the long campaign: reaching clinically proven success may entail a long campaign. However, already, on many fronts, the elements necessary for victory recently seem to be falling into place.

Background The SARS-Cov-2 Omicron variant demonstrates rapid spread but reduced disease severity. Studies evaluating lung imaging findings of Omicron infection versus non-Omicron infection remain lacking. Purpose To compare the Omicron variant with the SARS-CoV-2 Delta variant according to their chest CT radiologic pattern, biochemical parameters, clinical severity, and hospital outcomes after adjusting for vaccination status. Materials and Methods This retrospective study included hospitalized adult patients with reverse transcriptase-polymerase chain reaction test results positive for SARS-CoV-2, with CT pulmonary angiography performed within 7 days of admission between December 1, 2021, and January 14, 2022. Multiple readers performed blinded radiologic analyses that included RSNA CT classification, chest CT severity score (CTSS) (range, 0 [least severe] to 25 [most severe]), and CT imaging features, including bronchial wall thickening. Results A total of 106 patients (Delta group, n = 66; Omicron group, n = 40) were evaluated (overall mean age, 58 years ± 18 [SD]; 58 men). In the Omicron group, 37% of CT pulmonary angiograms (15 of 40 patients) were categorized as normal compared with 15% (10 of 66 patients) of angiograms in the Delta group ( P = .016). A generalized linear model was used to control for confounding variables, including vaccination status, and Omicron infection was associated with a CTSS that was 7.2 points lower than that associated with Delta infection (β = -7.2; 95% CI: -9.9, -4.5; P < .001). Bronchial wall thickening was more common with Omicron infection than with Delta infection (odds ratio [OR], 2.4; 95% CI: 1.01, 5.92; P = .04). A booster shot was associated with a protective effect for chest infection (median CTSS, 5; IQR, 0-11) when compared with unvaccinated individuals (median CTSS, 11; IQR, 7.5-14.0) ( P = .03). The Delta variant was associated with a higher OR of severe disease (OR, 4.6; 95% CI: 1.2, 26; P = .01) and admission to a critical care unit (OR, 7.0; 95% CI: 1.5, 66; P = .004) when compared with the Omicron variant. Conclusion The SARS-CoV-2 Omicron variant was associated with fewer and less severe changes on chest CT images compared with the Delta variant. Patients with Omicron infection had greater frequency of bronchial wall thickening but less severe disease and improved hospital outcomes when compared with patients with Delta infection. © RSNA, 2022 Online supplemental material is available for this article.

Sustaining the organisms, ecosystems and processes that underpin human wellbeing is necessary to achieve sustainable development. Here we define critical natural assets as the natural and semi-natural ecosystems that provide 90% of the total current magnitude of 14 types of nature's contributions to people (NCP), and we map the global locations of these critical natural assets at 2 km resolution. Critical natural assets for maintaining local-scale NCP (12 of the 14 NCP) account for 30% of total global land area and 24% of national territorial waters, while 44% of land area is required to also maintain two global-scale NCP (carbon storage and moisture recycling). These areas overlap substantially with cultural diversity (areas containing 96% of global languages) and biodiversity (covering area requirements for 73% of birds and 66% of mammals). At least 87% of the world's population live in the areas benefitting from critical natural assets for local-scale NCP, while only 16% live on the lands containing these assets. Many of the NCP mapped here are left out of international agreements focused on conserving species or mitigating climate change, yet this analysis shows that explicitly prioritizing critical natural assets and the NCP they provide could simultaneously advance development, climate and conservation goals., (© 2022. The Author(s).)

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8 + T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma., (© 2022. The Author(s).)

Background: Randomized controlled trials (RCT) of ultrafiltration (UF) have demonstrated conflicting results regarding its efficacy and safety., Objective: We reviewed 10 years of data for adjustable UF during heart failure hospitalizations in a real world cohort., Methods: We performed a retrospective, single center analysis of 335 consecutive patients treated with adjustable rate UF using the CHF Solutions Aquadex Flex Flo System from 2009 to 2019., Results: Compared to previous RCTs investigating UF, our cohort was older, with worse renal impairment and more antecedent HF hospitalizations in the year preceding therapy. Mean fluid removal with UF was 14.6 l. Mean weight loss with UF was 15.6 lbs (range 0.2-57 lbs) and was sustained at 1-2 week follow-up. Mean creatinine change upon stopping UF, at discharge and follow-up (mean 30 days) was +0.11 mg/dl, +0.07 mg/dl and +0.11 mg/dl, respectively. HF rehospitalizations at 30 days, 90 days and 1 year were 12.4 %, 14.9 % and 27.3 % respectively. On average patients had 1.74 fewer hospitalizations for HF in the year following UF when compared to 12 months preceding UF. Major bleeding defined as requiring discontinuation of anticoagulation occurred in 3.6 % of patients., Conclusions: Compared with previous UF trials, our study demonstrates that UF compares favorably for HF rehospitalizations, renal function response, and weight/volume loss. Importantly, our real world experience allowed for the adjustment of UF rate during therapy and we believe this is a major contributor to our favorable outcomes. In clinical practice, UF can be a safe and effective strategy for decongestion., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maureen Hummel reports financial support was provided by CHF Solutions (Nuwellis) for independent data analysis. Maureen Hummel reports a relationship with CHF Solutions (Nuwellis) that includes: speaking and lecture fees and travel reimbursement., (© 2022 Published by Elsevier Inc.)

Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms., (© 2022. The Author(s).)

Fish are an important source of bioavailable micronutrients and essential fatty acids, and capture fisheries have potential to substantially reduce dietary deficiencies. Vigorous debate has focused on trade and fishing in foreign waters as drivers of inequitable distribution of volume and value of fish, but their impact on nutrient supplies from fish is unknown. We analyze global catch, trade, and nutrient composition data for marine fisheries to quantify distribution patterns among countries with differing prevalence of inadequate nutrient intake. We find foreign fishing relocates 1.5 times more nutrients than international trade in fish. Analysis of nutrient flows among countries of different levels of nutrient intake shows fishing in foreign waters predominantly (but not exclusively) benefits nutrient-secure nations, an outcome amplified by trade. Next, we developed a nutritional vulnerability framework that shows those small island developing states and/or African nations currently benefiting from trade and foreign fishing, and countries with low adaptive capacity, are most vulnerable to future changes in nutrient supplies. Climate change exacerbates vulnerabilities for many nations. Harnessing the potential of global fisheries to address dietary deficiencies will require greater attention to nutrition objectives in fisheries’ licensing deals and trade negotiations.

Background: Accurate expected effective orifice area (EOA) values for balloon-expandable (BE) transcatheter heart valves (THV) are crucial for preventing patient-prosthesis mismatch (PPM) and assessment of THV function. Currently published reference EOAs, however, are based on transthoracic echocardiography (TTE), which may be subject to left ventricular outflow tract diameter underestimation and/or suboptimal THV Doppler interrogation. The objective of this study was to establish reference EOA values for BE THVs on the basis of Doppler and three-dimensional (3D) transesophageal echocardiography (TEE)., Methods: Two hundred twelve intraprocedural transesophageal echocardiographic examinations performed during BE THV implantation with optimal postimplantation Doppler and 3D imaging were retrospectively reviewed. Continuity equation-derived EOAs were compared with geometric orifice areas by 3D planimetry (GOA 3D ). Performance indices (i.e., EOA normalized to valve size) and PPM rates were determined. TTE-based EOAs obtained within 30 days were also calculated in a subset of 170 patients., Results: The average EOA for all BE THV valves (77% SAPIEN 3) was 2.3 ± 0.5 cm 2 , while the average EOA was 1.6 ± 0.2 cm 2 for 20-mm, 2.0 ± 0.2 cm 2 , for 23-mm, 2.5 ± 0.3 cm 2 for 26-mm, and 3.0 ± 0.3 cm 2 for 29-mm THV size (P < .001). Bland-Altman analysis demonstrated very good agreement between EOA and GOA 3D (bias -0.04 ± 0.15 cm 2 ). There were strong correlations between annular area and TEE-based EOA (R = 0.84) and GOA 3D (R = 0.87). The mean performance index was 47 ± 5% and was similar for all THV sizes (P = .21). EOAs based on TTE were smaller compared with those based on TEE, while the correlation with annular area (R = 0.67) and agreement with GOA 3D (bias -0.26 ± 0.43 cm 2 ) was not as strong. The overall PPM rate was 2% in the TEE cohort and 12% in the TTE cohort., Conclusions: EOAs for BE THVs based on intraprocedural Doppler and 3D TEE suggest that previously published TTE-based reference values for EOA are underestimated, while PPM rates may be overestimated. Our findings have important clinical implications for preimplantation decision-making and for the evaluation of THV hemodynamics and function during follow-up., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Aim: To determine if there is a difference in radiological, biochemical, or clinical severity between patients infected with Alpha-variant SARS-CoV-2 compared with those infected with pre-existing strains, and to determine if the computed tomography (CT) severity score (CTSS) for COVID-19 pneumonitis correlates with clinical severity and can prognosticate outcomes., Materials and Methods: Blinded CTSS scoring was applied to 137 hospital patients who had undergone both CT pulmonary angiography (CTPA) and whole-genome sequencing of SARS-CoV-2 within 14 days of CTPA between 1/12/20-5/1/21., Results: There was no evidence of a difference in imaging severity on CTPA, viral load, clinical parameters of severity, or outcomes between Alpha and preceding variants. CTSS on CTPA strongly correlates with clinical and biochemical severity at the time of CTPA, and with patient outcomes. Classifying CTSS into a binary value of "high" and "low", with a cut-off score of 14, patients with a high score have a significantly increased risk of deterioration, as defined by subsequent admission to critical care or death (multivariate hazard ratio [HR] 2.76, p<0.001), and hospital length of stay (17.4 versus 7.9 days, p<0.0001)., Conclusion: There was no evidence of a difference in radiological severity of Alpha variant infection compared with pre-existing strains. High CTSS applied to CTPA is associated with increased risk of COVID-19 severity and poorer clinical outcomes and may be of use particularly in settings where CT is not performed for diagnosis of COVID-19 but rather is used following clinical deterioration., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

One of the most pronounced effects of climate change on the world's oceans is the (generally) poleward movement of species and fishery stocks in response to increasing water temperatures. In some regions, such redistributions are already causing dramatic shifts in marine socioecological systems, profoundly altering ecosystem structure and function, challenging domestic and international fisheries, and impacting on human communities. Such effects are expected to become increasingly widespread as waters continue to warm and species ranges continue to shift. Actions taken over the coming decade (2021-2030) can help us adapt to species redistributions and minimise negative impacts on ecosystems and human communities, achieving a more sustainable future in the face of ecosystem change. We describe key drivers related to climate-driven species redistributions that are likely to have a high impact and influence on whether a sustainable future is achievable by 2030. We posit two different futures-a 'business as usual' future and a technically achievable and more sustainable future, aligned with the Sustainable Development Goals. We then identify concrete actions that provide a pathway towards the more sustainable 2030 and that acknowledge and include Indigenous perspectives. Achieving this sustainable future will depend on improved monitoring and detection, and on adaptive, cooperative management to proactively respond to the challenge of species redistribution. We synthesise examples of such actions as the basis of a strategic approach to tackle this global-scale challenge for the benefit of humanity and ecosystems., Supplementary Information: The online version contains supplementary material available at 10.1007/s11160-021-09641-3., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Crown 2021.)

NP 105-113 -B*07:02-specific CD8 + T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP 105-113 -B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP 105-113 -B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP 105-113 -B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design., (© 2021. The Author(s).)

Background: Biological evolution exhibits an extraordinary capability to adapt organisms to their environments. The explanation for this often takes for granted that random genetic variation produces at least some beneficial phenotypic variation in which natural selection can act. Such genetic evolvability could itself be a product of evolution, but it is widely acknowledged that the immediate selective gains of evolvability are small on short timescales. So how do biological systems come to exhibit such extraordinary capacity to evolve? One suggestion is that adaptive phenotypic plasticity makes genetic evolution find adaptations faster. However, the need to explain the origin of adaptive plasticity puts genetic evolution back in the driving seat, and genetic evolvability remains unexplained., Results: To better understand the interaction between plasticity and genetic evolvability, we simulate the evolution of phenotypes produced by gene-regulation network-based models of development. First, we show that the phenotypic variation resulting from genetic and environmental perturbation are highly concordant. This is because phenotypic variation, regardless of its cause, occurs within the relatively specific space of possibilities allowed by development. Second, we show that selection for genetic evolvability results in the evolution of adaptive plasticity and vice versa. This linkage is essentially symmetric but, unlike genetic evolvability, the selective gains of plasticity are often substantial on short, including within-lifetime, timescales. Accordingly, we show that selection for phenotypic plasticity can be effective in promoting the evolution of high genetic evolvability., Conclusions: Without overlooking the fact that adaptive plasticity is itself a product of genetic evolution, we show how past selection for plasticity can exercise a disproportionate effect on genetic evolvability and, in turn, influence the course of adaptive evolution., (© 2021. The Author(s).)

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8 + T cells. How sensitivity to ICB varies across CD8 + T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8 + T cell clones, identify baseline markers of CD8 + T cell clonal sensitivity, and chart how CD8 + T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8 + T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8 + T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8 + effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8 + T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8 + immune landscape in determining ICB response in metastatic melanoma.

Development of anti-drug antibodies (ADAs) can interfere with therapeutic monoclonal antibodies and may lead to drug neutralisation and clinical disease progression. Measurement of circulating drug levels and development of ADAs in the setting of anti-programmed cell death-1 agent pembrolizumab has not been well-studied. Enzyme-linked immunosorbent assays were used to measure pembrolizumab drug level and ADAs in 41 patients with melanoma at baseline, Time-point 1 (3 weeks) and Time-point 2 (21 weeks). Assay results were related to patient demographics and clinical outcome data at 6 months. The median pembrolizumab drug level at 3 weeks was 237 ng/μL and did not correlate with age, sex or body surface area.17/41 patients had an ADA detected at any timepoint, with the highest prevalence at Timepoint 1 (median concentration = 17 ng/μL). The presence of an ADA did not correlate with clinical progression at 6 months. 3/41 (7%) of patients displayed a falling pembrolizumab drug level and rising ADA titre between Timepoint 1 and 2 suggestive of a neutralising ADA. Pembrolizumab drug levels and ADAs can be readily measured. The rates of total and treatment-emergent ADAs may be higher in "real-word" settings than those previously reported. Larger studies are needed to determine effect of neutralising ADAs on long-term clinical outcome., (© 2021. The Author(s).)

Ribonucleotide reductase (RNR), which supplies the building blocks for DNA biosynthesis and its repair, has been linked to human diseases and is emerging as a therapeutic target. Here, we present a mechanistic investigation of triapine (3AP), a clinically relevant small molecule that inhibits the tyrosyl radical within the RNR β 2 subunit. Solvent kinetic isotope effects reveal that proton transfer is not rate-limiting for inhibition of Y122· of E. coli RNR β 2 by the pertinent 3AP-Fe(II) adduct. Vibrational spectroscopy further demonstrates that unlike inhibition of the β 2 tyrosyl radical by hydroxyurea, a carboxylate containing proton wire is not at play. Binding measurements reveal a low nanomolar affinity ( K d ∼ 6 nM) of 3AP-Fe(II) for β 2 . Taken together, these data should prompt further development of RNR inactivators based on the triapine scaffold for therapeutic applications.