The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate ...linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.
Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.
Of 468 assessable patients, 290 had Trop-2 expression data 64% (n = 151 SG) versus 60% (n = 139 TPC) and 292 had known BRCA1/2 mutation status 63% (n = 149 SG) versus 61% (n = 143 TPC). Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.
SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
•The majority of patients (80%) with mTNBC in the ASCENT study with available data had high/medium tumor Trop-2 expression.•Survival outcomes and ORRs were numerically higher in SG- versus TPC-treated patients with high/medium Trop-2 expression.•Benefit of SG in patients with high/medium Trop-2 expression was similar to that of overall primary efficacy population.•The small number of patients with low Trop-2 expression prevents definitive conclusions on benefit of SG in this subgroup.•Benefit of SG over TPC was also similar regardless of germline BRCA1/2 mutation status.
The New Horizons spacecraft's encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU
) revealed a contact-binary planetesimal. We investigated how ...Arrokoth formed and found that it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates that they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly because of dynamical friction and collisions within the cloud or later gas drag. Arrokoth's contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt and therefore informs the accretion processes that operated in the early Solar System.
Summary
Background
Excessive visceral adipose tissue has been associated with poorer outcomes in patients with inflammatory bowel disease.
Aim
To determine whether body composition is associated with ...outcome in a prospective study of post‐operative Crohn's disease patients.
Methods
The POCER study evaluated management strategies for prevention of post‐operative Crohn's disease recurrence; subjects were enrolled after resection of all macroscopic Crohn's disease and were randomised to early endoscopy and possible treatment escalation, or standard care. The primary endpoint was endoscopic recurrence at 18 months. 44 subjects with cross‐sectional abdominal imaging were studied, and body composition analysis performed using established techniques to measure visceral adipose tissue area, subcutaneous adipose tissue area, and skeletal muscle area.
Results
The body composition parameter with the greatest variance was visceral adipose tissue. Regardless of treatment, all subjects with visceral adipose tissue/height2 >1.5 times the gender‐specific mean experienced endoscopic recurrence at 18 months (compared to 47%) relative risk 2.1, 95% CI 1.5–3.0, P = 0.012. Waist circumference correlated strongly with visceral adipose tissue area (ρ = 0.840, P < 0.001). Low skeletal muscle was prevalent (41% of patients), but did not predict endoscopic recurrence; however, appendicular skeletal muscle indices correlated inversely with faecal calprotectin (ρ = 0.560, P = 0.046).
Conclusions
Visceral adiposity is an independent risk factor for endoscopic recurrence of Crohn's disease after surgery. Sarcopenia correlates with inflammatory biomarkers. Measures of visceral adipose tissue may help to stratify risk in post‐operative management strategies.
Linked ContentThis article is linked to Holt et al, and Stidham and Waljee papers. To view these articles visit https://doi.org/10.1111/apt.14102 and https://doi.org/10.1111/apt.14069.
One of the main diagnostic features of individuals with autism spectrum disorders is nonverbal behaviour difficulties during naturalistic social interactions. The 'Interactional Heterogeneity ...Hypothesis' of ASD proposes that the degree to which individuals share a common ground substantially influences their ability to achieve smooth social interactions.
To test this hypothesis, we filmed 29 autistic and 29 matched typically developed adults engaged in several conversational tasks. Windowed cross-lagged correlations were computed using the time series of motion energy of both individuals in a dyad. These coefficients were then compared across the three dyad types that were homo- or heterogenous with respect to diagnosis: pairs of two autistic individuals, two typically developed individuals or pairs of one autistic and one typically developed person.
We found that all dyad types achieved above-chance interpersonal synchrony, but that synchrony was more expressed in typical dyads compared to both autistic and mixed dyads.
The method presented here provides only one, albeit objective and robust, approach to explore synchrony. The methodological choices as well as the lack of consideration for other communication modalities may limit our interpretation of the findings. Moreover, the sample size is small with respect to exploring associations between synchrony and various outcome and social skill measures.
The present results do not provide support for the Interactional Heterogeneity Hypothesis given that autistic individuals do not coordinate better when interacting with another autistic individual, compared to when interacting with a typical individual.
Background
Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is ...unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis.
Methods
Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti‐inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index.
Results
Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean standard error of mean/hpf: diabetic, 2.28 0.16; idiopathic, 2.53 0.47; controls, 6.05 0.62; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti‐inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 0.32; idiopathic, 4.16 0.52; controls, 6.59 1.09; P=.04) and myenteric plexus (diabetic, 3.83 0.27; idiopathic, 3.59 0.68; controls, 7.46 0.51; P=.004). There was correlation between the number of ICC and CD206‐positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04).
Conclusion
Loss of antral CD206‐positive anti‐inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.
Animal studies have highlighted an important role of macrophages in development of delayed gastric emptying. However, their role in human gastroparesis is unclear. Upon assessment of full thickness gastric antrum biopsies, both diabetic and idiopathic gastroparesis patients showed a loss of CD206‐positive anti‐inflammatory macrophages as compared to controls. This correlated with loss of ICC suggesting a role of innate immune cells in pathophysiology of human gastroparesis.
Increasingly governments around the world are experimenting with initiatives in transparency or 'open government'. These involve a variety of measures including the announcement of more user-friendly ...government websites, greater access to government data, the extension of freedom of information legislation and broader attempts to involve the public in government decision making. However, the role of the media in these initiatives has not hitherto been examined. This volume analyses the challenges and opportunities presented to journalists as they attempt to hold governments accountable in an era of professed transparency. In examining how transparency and open government initiatives have affected the accountability role of the press in the US and the UK, it also explores how policies in these two countries could change in the future to help journalists hold governments more accountable. This volume will be essential reading for all practising journalists, for students of journalism or politics, and for policymakers.
We theoretically investigate the properties of holes in a Six Ge1−x / Ge / Six Ge1−x quantum well in a perpendicular magnetic field that make them advantageous as qubits, including a large (> 100 ...meV) intrinsic splitting between the light and heavy hole bands, a very light (∼ 0.05 m0) in-plane effective mass, consistent with higher mobilities and tunnel rates, and larger dot sizes that could ameliorate constraints on device fabrication. Compared to electrons in quantum dots, hole qubits do not suffer from the presence of nearby quantum levels (e.g., valley states) that can compete with spins as qubits. The strong spin-orbit coupling in Ge quantum wells may be harnessed to implement electric-dipole spin resonance, leading to gate times of several nanoseconds for single-qubit rotations. The microscopic mechanism of this spin-orbit coupling is discussed, along with its implications for quantum gates based on electric-dipole spin resonance, stressing the importance of coupling terms that arise from the underlying cubic crystal field. Our results provide a theoretical foundation for recent experimental advances in Ge hole-spin qubits.
Background
Factors associated with abdominal pain in gastroparesis are incompletely evaluated and comparisons of pain vs other symptoms are limited. This study related pain to clinical factors in ...gastroparesis and contrasted pain/discomfort‐ with nausea/vomiting‐predominant disease.
Methods
Clinical and scintigraphy data were compared in 393 patients from seven centers of the NIDDK Gastroparesis Clinical Research Consortium with moderate‐severe (Patient Assessment of Upper Gastrointestinal Disorders Symptoms PAGI‐SYM score ≥3) vs none‐mild (PAGI‐SYM < 3) upper abdominal pain and predominant pain/discomfort vs nausea/vomiting.
Key Results
Upper abdominal pain was moderate‐severe in 261 (66%). Pain/discomfort was predominant in 81 (21%); nausea/vomiting was predominant in 172 (44%). Moderate‐severe pain was more prevalent with idiopathic gastroparesis and with lack of infectious prodrome (P ≤ 0.05) and correlated with scores for nausea/vomiting, bloating, lower abdominal pain/discomfort, bowel disturbances, and opiate and antiemetic use (P < 0.05), but not gastric emptying or diabetic neuropathy or control. Gastroparesis severity, quality of life, and depression and anxiety were worse with moderate‐severe pain (P ≤ 0.008). Factors associated with moderate‐severe pain were similar in diabetic and idiopathic gastroparesis. Compared to predominant nausea/vomiting, predominant pain/discomfort was associated with impaired quality of life, greater opiate, and less antiemetic use (P < 0.01), but similar severity and gastric retention.
Conclusions & Inferences
Moderate‐severe abdominal pain is prevalent in gastroparesis, impairs quality of life, and is associated with idiopathic etiology, lack of infectious prodrome, and opiate use. Pain is predominant in one fifth of gastroparetics. Predominant pain has at least as great an impact on disease severity and quality of life as predominant nausea/vomiting.
The prevalence of disease-driven mass mortality events is increasing, but our understanding of spatial variation in their magnitude, timing and triggers are often poorly resolved. Here, we use a ...novel range-wide dataset comprised 48 810 surveys to quantify how sea star wasting disease affected
, the sunflower sea star, across its range from Baja California, Mexico to the Aleutian Islands, USA. We found that the outbreak occurred more rapidly, killed a greater percentage of the population and left fewer survivors in the southern half of the species's range.
now appears to be functionally extinct (greater than 99.2% declines) from Baja California, Mexico to Cape Flattery, Washington, USA and exhibited severe declines (greater than 87.8%) from the Salish Sea to the Gulf of Alaska. The importance of temperature in predicting
distribution rose more than fourfold after the outbreak, suggesting latitudinal variation in outbreak severity may stem from an interaction between disease severity and warmer waters. We found no evidence of population recovery in the years since the outbreak. Natural recovery in the southern half of the range is unlikely over the short term. Thus, assisted recovery will probably be required to restore the functional role of this predator on ecologically relevant time scales.
Background
Wireless motility capsule (WMC) findings are incompletely defined in suspected gastroparesis. We aimed to characterize regional WMC transit and contractility in relation to scintigraphy, ...etiology, and symptoms in patients undergoing gastric emptying testing.
Methods
A total of 209 patients with gastroparesis symptoms at NIDDK Gastroparesis Consortium centers underwent gastric scintigraphy and WMCs on separate days to measure regional transit and contractility. Validated questionnaires quantified symptoms.
Key Results
Solid scintigraphy and liquid scintigraphy were delayed in 68.8% and 34.8% of patients; WMC gastric emptying times (GET) were delayed in 40.3% and showed 52.8% agreement with scintigraphy; 15.5% and 33.5% had delayed small bowel (SBTT) and colon transit (CTT) times. Transit was delayed in ≥2 regions in 23.3%. Rapid transit was rarely observed. Diabetics had slower GET but more rapid SBTT versus idiopathics (P ≤ .02). GET delays related to greater scintigraphic retention, slower SBTT, and fewer gastric contractions (P ≤ .04). Overall gastroparesis symptoms and nausea/vomiting, early satiety/fullness, bloating/distention, and upper abdominal pain subscores showed no relation to WMC transit. Upper and lower abdominal pain scores (P ≤ .03) were greater with increased colon contractions. Constipation correlated with slower CTT and higher colon contractions (P = .03). Diarrhea scores were higher with delayed SBTT and CTT (P ≤ .04).
Conclusions & Inferences
Wireless motility capsules define gastric emptying delays similar but not identical to scintigraphy that are more severe in diabetics and relate to reduced gastric contractility. Extragastric transit delays occur in >40% with suspected gastroparesis. Gastroparesis symptoms show little association with WMC profiles, although lower symptoms relate to small bowel or colon abnormalities.
Wireless motility capsule (WMC) findings in suspected gastroparesis and relations to symptoms have been poorly defined. Evaluation of patients with gastroparesis symptoms revealed gastric emptying delays with WMCs that were similar to scintigraphy, were related to reduced contractility, and were often associated with extragastric or generalized transit delays; symptoms correlated poorly with WMC profiles. These findings provide insight into motor abnormalities in gastroparesis pathogenesis and form a basis for future investigations studying the impact of WMC testing on clinical care.
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