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The South Nicholson National Drilling Initiative (NDI) Carrara 1 stratigraphic drill hole was completed in late 2020, as a collaboration between Geoscience Australia, the Northern Territory Geological Survey (NTGS), and the MinEx CRC. The drilling aimed to gather new subsurface data on the potential mineral and energy resources in the newly identified Carrara Sub-basin. NDI Carrara 1 is located in the eastern Northern Territory, on the western flanks of the Carrara Sub-basin on the South Nicholson Seismic line, reaching a total depth of 1751 m, intersecting ca. 630 m of Cambrian Georgina Basin overlying ca. 1100 m of Proterozoic carbonates, black shales and minor siliciclastics (https://portal.ga.gov.au/bhcr/minerals/648482). Following a public data release of the borehole completion report, CSIRO was contracted by Geoscience Australia (GA) under the Exploring for the Future program to analyse samples from NDI Carrara 1 for quantitative bulk and clay fraction analysis. This report presents results for quantitative bulk and clay (

A semi-experimental equilibrium structure (reSE) of pyridazine (o-C4H4N2) has been determined using the rotational spectra of 18 isotopologues. Spectroscopic constants of four isotopologues are reported for the first time (measured from 235 to 360 GHz), while spectroscopic constants for previously reported isotopologues are improved by extending the frequency coverage (measured from 130 to 375 GHz). The experimental values of the ground-state rotational constants (A0, B0, and C0) from each isotopologue were converted to determinable constants (A0″, B0″, and C0″), which were then corrected for the effects of vibration-rotation interactions and electron-mass distributions using CCSD(T)/cc-pCVTZ calculations. The resultant reSE for pyridazine determines bond distances to within 0.001 A and bond angles within 0.04°, a reduction in the statistical uncertainties by at least a factor of two relative to the previously reported reSE. The improvement in precision appears to be largely due to the use of higher-level theoretical calculations of the vibration-rotation and electron-mass effects, though the incorporation of the newly measured isotopologues ([4-2H, 4-13C]-, [4-2H, 5-13C]-, [4-2H, 6-13C]-, and [4,5-2H, 4-13C]-pyridazine) is partially responsible for the improved determination of the hydrogen-containing bond angles. The computed equilibrium structure (re) (CCSD(T)/cc-pCV5Z) and a "best theoretical estimate" of the equilibrium structure (re) both agree with the updated reSE structure within the statistical experimental uncertainty (2σ) of each structural parameter.

Maintenance of mitochondrial health, which is supported in part by dietary antioxidants such as selenium (Se) and vitamin E (vitE), is pertinent to optimizing athletic performance. Deficiencies in Se and vitE negatively impact muscle health but mitochondrial adaptations to various levels of dietary Se and vitE are poorly understood. Young Quarter Horses (mean ± SD: 17.6 ± 0.9 mo) undergoing submaximal exercise training were used to test the hypothesis that a proprietary antioxidant blend containing elevated Se yeast (EconomasE, Alltech, Inc., Nicholasville, KY) would improve mitochondrial characteristics compared to Se at current requirements, even with reduced vitE intake. Horses were balanced by age, sex, body weight (BW), and farm of origin and randomly assigned to one of three custom-formulated concentrates fed at 1% BW (dry matter, DM basis) for 12 wk: 1) 100 IU vitE/kg DM and 0.1 mg Se/kg DM (CON, n = 6); 2) no added vitE plus EconomasE to provide 0.1 mg Se/kg DM (ESe1, n = 6); or 3) no added vitE plus EconomasE to provide 0.3 mg Se/kg DM (ESe3, n = 6). Samples collected at week 0 and 12 were analyzed for serum Se and middle gluteal glutathione peroxidase (GPx) and mitochondrial enzyme activities by kinetic colorimetry and mitochondrial capacities by high-resolution respirometry. Data were analyzed using mixed linear models in SAS v9.4 with repeated measures (time) and fixed effects of time, diet, and time × diet; horse(diet) served as a random effect. Serum Se tended to increase in all horses by week 12 (P = 0.08) but was unaffected by diet. Muscle GPx activity remained similar among all horses throughout the duration of the study. Mitochondrial volume density (citrate synthase [CS] activity), integrative function (cytochrome c oxidase [CCO] activity per mg protein), and integrative (per mg tissue) oxidative (P) and electron transfer (E) capacities increased from week 0 to 12 in all horses (P ≤ 0.01). Intrinsic (relative to CS) CCO activity decreased in all horses (P = 0.001), while intrinsic P and E capacities decreased only in ESe1 horses from week 0 to 12 (P ≤ 0.002). These results suggest that feeding EconomasE to provide 0.3 mg Se/kg DM may prevent adverse effects of removing 100 IU dietary vitE/kg DM on mitochondria in young horses. More research is needed to determine optimal dietary Se and vitE levels in performance horses to maximize mitochondrial energy production.Mitochondria, colloquially referred to as the powerhouses of the cell, are essential for sustained energy production, which is particularly important for athletic performance. During exercise, reactive oxygen species (ROS) are produced as a normal byproduct of muscle contraction. ROS act as critical signaling molecules and are essential to stimulate adaptation to exercise and other stressors. However, if excess ROS are produced and not sequestered by antioxidants, they may damage cellular components such as lipids, proteins, and DNA. Selenium (Se) and vitamin E (vitE) are two primary dietary antioxidants that aid in quenching excess ROS. To evaluate the impact of Se and vitE on mitochondria, three diets differing in Se and vitE levels were provided to lightly exercising young horses for 12 wk. Skeletal muscle mitochondrial capacity was negatively impacted by the reduction of dietary vitE, which was rescued with elevated dietary Se. The results highlight the importance of determining optimal levels of minerals and vitamins in performance horse diets to ensure proper energy production during exercise.

Three cyanobutadiene isomers have been synthesized and their rotational spectra analyzed in the 130-375 GHz frequency range. These species, which are close analogues of known interstellar molecules and are isomers of the heterocyclic aromatic molecule pyridine (C5H5N), offer the opportunity of revealing important insights concerning the chemistry in astronomical environments. The s-trans conformers of E-1-cyano-1,3-butadiene and Z-1-cyano-1,3-butadiene are observed, while both the anti-clinal and syn-periplanar conformers of 4-cyano-1,2-butadiene are evident in the rotational spectra. Over 1000 transitions for s-trans-Z-1-cyano-1,3-butadiene and for syn-periplanar-4-cyano-1,2-butadiene are fit to an octic, distorted-rotor Hamiltonian with low uncertainty (

Hydrazoic acid (HN

To test the hypothesis that complexed trace mineral supplementation would increase antioxidant capacity and decrease muscle oxidative stress and damage in young horses entering an exercise training program, Quarter Horses (mean $$\pm$$ ± SD; 9.7 ± 0.7 mo) balanced by age, sex, and BW were assigned to receive complexed (CTM; n = 8) or inorganic (INORG; n = 8) trace minerals at -12 week relative to this study. Blood and muscle samples were collected before (week 0) and after 12 week of light exercise training surrounding a 1.5-h trailer stressor. Muscle glutathione peroxidase (GPx) activity was higher for CTM than INORG horses (P ≤ 0.0003) throughout the study. Following both trailer stressors, serum creatine kinase increased (P P superoxide dismutase 2, and whole blood GPx activity increased (P$$\le$$ ≤ 0.003) following trailering but trailering did not affect these measures at week 12. Young horses supplemented with CTM had higher muscle GPx activity than horses receiving INORG, but CTM did not affect damage markers following a stressor. Dietary CTM may be useful for improving antioxidant capacity during exercise training in young equine athletes.

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.Patients and methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors.Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Hidden Markov models have become a popular time series method for the analysis of GPS tracked animals. Their advantage for identifying latent behavioural states compared with Independent Mixture models is that they take into account the time series dependency of successive displacement distances by the tracked animals. However, little is known about how the analysis results may differ depending on which of these approaches is used. We compared the results and interpretations obtained from fitting Hidden Markov and Independent Mixture models to simulated movement data as well as to field data recording the hourly movements of sable antelope and buffalo within the Kruger National Park, South Africa. Hidden Markov models consistently yielded narrower confidence intervals around parameters and smaller standard errors than simpler time independent mixture models, but for some data the improvement was marginal and the Independent Mixture model provided an adequate alternative for identifying the latent behavioural states of the animal. In general, it is expected Hidden Markov models will provide the better balance between model complexity and extensibility for animal movement modelling from a statistical perspective. However, in some cases, Independent Mixture models could provide an adequate alternative method and might be more faithful biologically. Keywords: Activity states, African buffalo, Hidden Markov models, Independent mixture models, Latent states

The Unfinished: Stone Carvers at Work on the Indian Subcontinent. By Vidya Dehejia and Peter Rockwell. New Delhi: rOLI BOOkS, 2016. Pp. 280, illus.

A semi-experimental equilibrium structure (

The pure rotational spectrum of thiazole (c-C(3)H(3)NS, C(s)) has been studied in the millimeter-wave region from 130 to 375 GHz. Nearly 4800 newly measured rotational transitions for the ground vibrational state of the main isotopologue were combined with previously reported measurements and least-squares fit to a complete sextic Hamiltonian. Transitions for six singly substituted heavy-atom isotopologues ((13)C, (15)N, (33)S, (34)S) were observed at natural abundance and likewise fit. Several deuterium-enriched samples were prepared, which gave access to the rotational spectra of 16 additional isotopologues, 14 of which had not been previously studied. The rotational spectra of each isotopologue were fit to A- and S-reduced distorted-rotor Hamiltonians in the I(r) representation. The experimental values of the ground-state rotational constants (A(0), B(0), and C(0)) from each isotopologue were converted to determinable constants (A(0)″, B(0)″, and C(0)″), which were corrected for effects of vibration–rotation interactions and electron-mass distributions using coupled-cluster singles, doubles, and perturbative triples calculations [CCSD(T)/cc-pCVTZ]. The moments of inertia from the resulting constants (A(e), B(e), and C(e)) of 24 isotopologues were used to determine the precise semi-experimental equilibrium structure (r(e)(SE)) of thiazole. As a basis for comparison, a purely theoretical equilibrium structure was estimated by an electronic structure calculation [CCSD(T)/cc-pCV5Z] that was subsequently corrected for extrapolation to the complete basis set, electron correlation beyond CCSD(T), relativistic effects, and the diagonal Born–Oppenheimer correction. The precise r(e)(SE) structure is compared to the resulting “best theoretical estimate” structure. Some, but not all, of the best theoretical r(e) structural parameters fall within the narrow statistical limits (2σ) of the r(e)(SE) results. The possible origin of the discrepancies between the best theoretical estimate r(e) and semi-empirical r(e)(SE) structures is discussed.

In aged humans, low-intensity exercise increases mitochondrial density, function and oxidative capacity, decreases the prevalence of hybrid fibers, and increases lean muscle mass, but these adaptations have not been studied in aged horses. Effects of age and exercise training on muscle fiber type and size, satellite cell abundance, and mitochondrial volume density (citrate synthase activity; CS), function (cytochrome c oxidase activity; CCO), and integrative (per mg tissue) and intrinsic (per unit CS) oxidative capacities were evaluated in skeletal muscle from aged (n = 9; 22 ± 5 yr) and yearling (n = 8; 9.7 ± 0.7 mo) horses. Muscle was collected from the gluteus medius (GM) and triceps brachii at wk 0, 8, and 12 of exercise training. Data were analyzed using linear models with age, training, muscle, and all interactions as fixed effects. At wk 0, aged horses exhibited a lower percentage of type IIx (p = 0.0006) and greater percentage of hybrid IIa/x fibers (p = 0.002) in the GM, less satellite cells per type II fiber (p = 0.03), lesser integrative and intrinsic (p≤ 0.04) CCO activities, lesser integrative oxidative phosphorylation capacity with complex I (PCI; p = 0.02) and maximal electron transfer system capacity (ECI+II; p = 0.06), and greater intrinsic PCI, ECI+II, and electron transfer system capacity with complex II (ECII; p≤ 0.05) than young horses. The percentage of type IIx fibers increased (p < 0.0001) and of type IIa/x fibers decreased (p = 0.001) in the GM, and the number of satellite cells per type II fiber increased (p = 0.0006) in aged horses following exercise training. Conversely, the percentage of type IIa/x fibers increased (p ≤ 0.01) and of type IIx fibers decreased (p ≤ 0.002) in young horses. Integrative maximal oxidative capacity (p ≤ 0.02), ECI+II (p ≤ 0.07), and ECII (p = 0.0003) increased for both age groups from wk 0 to 12. Following exercise training, aged horses had a greater percentage of IIx (p ≤ 0.002) and lesser percentage of IIa/x fibers (p ≤ 0.07), and more satellite cells per type II fiber (p = 0.08) than young horses, but sustained lesser integrative and intrinsic CCO activities (p≤ 0.04) and greater intrinsic PCI, ECI+II, and ECII (p≤ 0.05). Exercise improved mitochondrial measures in young and aged horses; however, aged horses showed impaired mitochondrial function and differences in adaptation to exercise training.

Incomplete fusion of the optic fissure leads to ocular coloboma, a congenital eye defect that affects up to 7.5 per 10,000 births and accounts for up to 10 percent of childhood blindness. The molecular and cellular mechanisms that facilitate optic fissure fusion remain elusive. We have profiled global gene expression during optic fissure morphogenesis by transcriptome analysis of tissue dissected from the margins of the zebrafish optic fissure and the opposing dorsal retina before (32 hours post fertilisation, hpf), during (48 hpf) and after (56 hpf) optic fissure fusion. Differential expression analysis between optic fissure and dorsal retinal tissue resulted in the detection of several known and novel developmental genes. The expression of selected genes was validated by qRT-PCR analysis and localisation investigated using in situ hybridisation. We discuss significantly overrepresented functional ontology categories in the context of optic fissure morphogenesis and highlight interesting transcripts from hierarchical clustering for subsequent analysis. We have identified netrin1a (ntn1a) as highly differentially expressed across optic fissure fusion, with a resultant ocular coloboma phenotype following morpholino antisense translation-blocking knockdown and downstream disruption of atoh7 expression. To support the identification of candidate genes in human studies, we have generated an online open-access resource for fast and simple quantitative querying of the gene expression data. Our study represents the first comprehensive analysis of the zebrafish optic fissure transcriptome and provides a valuable resource to facilitate our understanding of the complex aetiology of ocular coloboma.

BackgroundAdjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma.MethodsAssociations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab/pembrolizumab±low-dose/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1.ResultsWith a median follow-up of 19.3 months, 37/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39−CD103−PD-1−CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1 year.ConclusionsAdjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer.

A helium-microplasma ion source (Glow Flow) has been developed and characterised. It is engineered to be a simple design, of low-cost and can be readily retrofitted to most modern mass spectrometers. Initial assessment of its performance has shown it to be robust, reproducible and of high sensitivity. Glow Flow provides broad non-specific detection of samples from polar through to non-polar chemistries making it of wide utility. A study of persistent organic pollutants, polyaromatic hydrocarbons, low average-molecular-mass polymers (polyethyleneimine, polyethylene glycol, and polypropylene glycol) and a complex mixture of fatty-acid methyl esters by direct sample introduction using a nebulised heated nitrogen flow was conducted. The ability to make quantitative measurement was investigated using methyl stearate and a linear calibration plot gave a R2 = 0.999 and limit-of-detection of ∼100 fmol. This design is extremely stable, in operation. Typical ions commonly observed are intense protonated molecule ions, radical molecular ions, hydride abstracted ions, and oxygen adduct ions. At present this system is valuable to apply to small molecule analysis (m/z

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were 3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Conjugated linoleic acid (CLA) improves oxidative stress and mitochondrial biogenesis in various species but has not been thoroughly investigated in horses. We collected blood and muscle samples from lightly exercising horses before and 6 and 12 wk after receiving either soybean oil (CON; n = 5) or CLA (CLA; n = 5) supplementation. Samples were analyzed for markers of mitochondrial characteristics, antioxidant status, oxidative stress, and muscle damage. Data were analyzed using a linear model with repeated measures. In the triceps brachii (TB), citrate synthase (CS) activity was higher in CON than CLA horses (P = 0.003) but was unaffected by diet in the gluteus medius (GM). Integrative (relative to mg protein) cytochrome c oxidase (CCO) activity was higher in TB than the GM (P < 0.0001), while intrinsic (relative to CS) CCO was lower in the TB than the GM (P = 0.02) and tended to be lower in CON than CLA horses (P = 0.06). Neither CS nor integrative CCO activities were affected by time. In the GM, superoxide dismutase activity tended to increase in CON through week 12 (P = 0.10). Over both muscle groups, glutathione peroxidase activity tended to be higher in CON compared with CLA at week 12 (P = 0.06). Malondialdehyde was higher in the TB than the GM (P = 0.0004) but was unaffected by diet, while serum creatine kinase activity tended to be lower in CLA than CON horses (P = 0.07). These results suggest that CLA supplementation may lead to mitochondrial adaptations and prevent myofiber perturbation in skeletal muscle of young, lightly exercised horses.

Background Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification.In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months.During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

Introduction Condomless anal intercourse (AI) confers a far greater likelihood of HIV transmission than condomless vaginal intercourse (VI). However, little is known about AI practice over the life course of women, to what extent AI practice is condom-protected, and whether it is associated with other HIV risk behaviors. We aim to describe longitudinal AI practice among HIV-seronegative women and to identify subgroups with distinct trajectories of AI practice. Methods Using data from the Women's Interagency HIV Study, an observational cohort of US women with or at risk for HIV, we described AI practice among HIV-seronegative participants. Group-based trajectory modeling was used to identify distinct AI trajectories. We used multinomial regression to examine associations between baseline characteristics and trajectory group membership. Results A third of the 1,085 women in our sample reported any AI over follow-up (median follow-up = 14 years). AI decreased more sharply with age compared to VI. Consistent condom use during AI was low: twice the proportion of women never reported using condoms consistently during AI compared to during VI. 5 trajectory groups were identified: AI & VI persistors (N = 75) practiced AI and VI consistently over follow-up (AI & VI desistors (N = 169) tended to practice AI and VI when young only, while VI persistors (N = 549), VI desistors (N = 167), and AI & VI inactives (N = 125) reported varying levels of VI practice, but little AI. AI & VI persistors reported multiple male partners and exchange sex at more visits than other groups. Women who identified as bisexual/lesbian (vs heterosexual), who had ever experienced physical and sexual violence (vs never), and/or who reported above the median number of lifetime male sex partners (vs median or below) had approximately twice the odds of being AI & VI persistors than being VI persistors. Conclusions We identified a small subgroup of women who practice AI and report inconsistent condom use along with other risk behaviors throughout the life course; they may therefore particularly benefit from ongoing access to HIV prevention services including pre-exposure prophylaxis.

Continuous structural parameterization (CSP) is a proposed method for approximating different numerical model parameterizations of the same process as functions of the same grid‐scale variables. This allows systematic comparison of parameterizations with each other and observations or resolved simulations of the same process. Using the example of two convection schemes running in the Met Office Unified Model (UM), we show that a CSP is able to capture concisely the broad behavior of the two schemes, and differences between the parameterizations and resolved convection simulated by a high resolution simulation. When the original convection schemes are replaced with their CSP emulators within the UM, basic features of the original model climate and some features of climate change are reproduced, demonstrating that CSP can capture much of the important behavior of the schemes. Our results open the possibility that future work will estimate uncertainty in model projections of climate change from estimates of uncertainty in simulation of the relevant physical processes. Plain Language Summary Numerical models are used to provide estimates of future weather and climate change. The models contain “parameterizations,” which are algorithms that simulate the effect of processes too small or poorly understood to represent using physical equations. Although they are based as much as possible on physics, parameterizations are a large source of modeling uncertainty because there can be large disagreements on how to best represent a given process. The method and even the variables used by two different parameterizations may differ. It is therefore very difficult to know how different parameterizations cause numerical models to produce different results and whether the parameterizations we have are adequate and span the range of uncertainty concerning our knowledge of the processes they represent. Using the example of small‐scale atmospheric convection linked to rain and thunderstorms, this paper describes a mathematical method for expressing different parameterizations within the same framework. This allows easy but formal mathematical comparison of different parameterizations and gives future work the potential to understand whether our parameterizations perform as they should in conjunction with future observations.

In this chapter, I examine the most prominent rock-reliefs at the site of Badami that are carved on a colossal boulder located at the eastern end of Badami’s Agastya tank. Depicted on this rock are a series of Hindu deities: Varaha, Ganesha, the trimurti (i.e., Brahma, Shiva, and Vishnu), Durga Mahisasuramardini, and Narasimha. Nagas (serpent deities) are also carved on this rock, as well as many linga-shrines. Given the plethora of caves and temples at the site, why carve images on a boulder and why carve these specific deities and temple forms? Were these images worshipped in similar ways as enshrined deities at the site, or might they serve other purposes? In contrast to other scholarly approaches to Badami which tend to focus on the roles of the political elite, I am interested in how these rock-reliefs might shed light on the site’s larger cultural and devotional landscapes. In my examinations of these rock-reliefs, I argue that they form a dialogue with other monuments at the site, and that this dialogue reflects the interests of a diverse social base that includes many voices—artists, local residents, ascetics, and agrarian communities.

Temperamental cattle tend to yield carcasses of poorer quality, and Brahman cattle are reportedly more temperamental than non-indicus cattle breeds. A potential link between temperament and product quality may be mitochondrial activity. We hypothesized that mitochondrial measures would be greater in temperamental compared with calm heifers and that the relationships between temperament and mitochondria would persist as heifers age. Serum cortisol and skeletal muscle (longissimus thoracis [LT] and trapezius [TRAP]) mitochondrial profiles and antioxidant activities were quantified from the same calm (n = 6) and temperamental (n = 6) Brahman heifers at 8, 12, and 18 mo of age. Data were analyzed using a mixed model ANOVA in SAS (9.4) with repeated measures. Serum cortisol was greater in temperamental compared with calm heifers throughout the study (P = 0.02). Mitochondrial volume density (citrate synthase [CS] activity) increased over time (P < 0.0001) but was similar between temperament and muscle groups. Mitochondrial function (cytochrome c oxidase activity) was greatest in the temperamental LT at 8 mo of age (P ≤ 0.0006), greatest in the temperamental TRAP at 18 mo of age (P ≤ 0.003), and did not differ by temperament at 12 mo of age. Integrative (relative to tissue wet weight) mitochondrial oxidative phosphorylation capacity with complex I substrates (PCI), PCI plus complex II substrate (PCI+II), noncoupled electron transfer system capacity (ECI+II), and E with functional complex II only (ECII) were greater in the TRAP than LT for calm heifers at all ages (P ≤ 0.002), but were similar between muscle groups in temperamental heifers. Overall, calm heifers tended to have greater intrinsic (relative to CS activity) PCI and flux control of PCI+II (P ≤ 0.1) than temperamental heifers, indicating greater utilization of complex I paired with greater coupling efficiency in calm heifers. Within the LT, integrative PCI+II was greater (P = 0.05) and ECI+II tended to be greater (P = 0.06) in temperamental compared with calm heifers. From 8- to 18-mo old, glutathione peroxidase (GPx) activity decreased (P < 0.0001) and superoxide dismutase activity increased (P = 0.02), and both were similar between muscle groups. The activity of GPx was greater in temperamental compared with calm heifers at 8 (P = 0.004) but not at 12 or 18 mo of age. These results detail divergent skeletal muscle mitochondrial characteristics of live Brahman heifers according to temperament, which should be further investigated as a potential link between temperament and product quality.