Symptom persistence and recovery among COVID-19 survivors during a limited outbreak in Canterbury, New Zealand: a prospective cohort study.

BACKGROUND: In Canterbury, near complete identification of coronavirus disease 2019 (COVID-19) cases during a limited outbreak provides unique insights into sequelae. AIMS: The current study aimed to measure symptom persistence, time to return to normal activity, generalised anxiety and health-related quality of life (HrQoL) among COVID-19 survivors compared with uninfected participants. METHODS: The authors conducted a prospective cohort study of people tested for COVID-19 by reverse transcriptase polymerase chain reaction of nasopharyngeal swabs from 1 March to 30 June 2020. They enrolled participants who tested positive and negative at a 1:2 ratio, and administered community-acquired pneumonia, 7-item generalised anxiety disorder (GAD-7) and HrQoL (RAND-36) questionnaires. RESULTS: The authors recruited 145 participants, 48 with COVID-19 and 97 without COVID-19. The mean time from COVID-19 testing to completing the health questionnaire was 306 days. The mean age of patients was 46.7 years, and 70% were women. Four (8%) COVID-19-positive and eight (8%) COVID-19-negative participants required hospitalisation. Fatigue (30/48 [63%] vs 13/97 [13%]; P < 0.001), dyspnoea (13/48 [27%] vs 6/97 [6%]; P < 0.001) and chest pain (10/48 [21%] vs 1/97 [1%]; P < 0.001) were persistent in those with COVID-19. Fewer COVID-19-positive participants returned to normal activity levels (35/48 [73%] vs 94/97 97%; P < 0.001), with longer times taken (median 21 vs 14 days; P = 0.007). The GAD-7 and RAND-36 scores of both groups were similar across all anxiety and HrQoL subscales. CONCLUSIONS: Persistent symptoms and longer recovery times were found in COVID-19 survivors, but not impaired generalised anxiety levels or HrQoL compared with COVID-19-uninfected participants.

Phase 1 Combination Study of the CHK1 Inhibitor Prexasertib and the PARP Inhibitor Olaparib in High-grade Serous Ovarian Cancer and Other Solid Tumors.

PURPOSE: Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with de novo or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition. PATIENTS AND METHODS: This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1-5 and 15-19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments. RESULTS: Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m2 i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with BRCA1-mutant, PARP inhibitor-resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure. CONCLUSIONS: Prexasertib combined with olaparib has preliminary clinical activity in BRCA-mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.

Immune modulating activity of the CHK1 inhibitor prexasertib and anti-PD-L1 antibody LY3300054 in patients with high-grade serous ovarian cancer and other solid tumors.

BACKGROUND: Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation. METHODS: This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform. RESULTS: Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m2 prexasertib and 700 mg LY3300054. Dose-limiting toxicities included one episode each of febrile neutropenia (Arm C) and grade 4 neutropenia lasting > 5 days (Arm B). One patient had immune-related AST/ALT elevation after 12 cycles. Three patients with CCNE1-amplified, high-grade serous ovarian cancer (HGSOC) achieved partial response (PR), 2 lasting > 12 months; a fourth such patient maintained stable disease > 12 months. Analysis of peripheral blood demonstrated evidence of CD8 + T-cell activation in response to treatment. CONCLUSIONS: Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018.

Past East Asian monsoon evolution controlled by paleogeography, not CO2.

The East Asian monsoon plays an integral role in human society, yet its geological history and controlling processes are poorly understood. Using a general circulation model and geological data, we explore the drivers controlling the evolution of the monsoon system over the past 150 million years. In contrast to previous work, we find that the monsoon is controlled primarily by changes in paleogeography, with little influence from atmospheric CO2. We associate increased precipitation since the Late Cretaceous with the gradual uplift of the Himalayan-Tibetan region, transitioning from an ITCZ-dominated monsoon to a sea breeze-dominated monsoon. The rising region acted as a mechanical barrier to cold and dry continental air advecting into the region, leading to increasing influence of moist air from the Indian Ocean/South China Sea. We show that, apart from a dry period in the middle Cretaceous, a monsoon system has existed in East Asia since at least the Early Cretaceous.

Coupling of palaeontological and neontological reef coral data improves forecasts of biodiversity responses under global climatic change.

Reef corals are currently undergoing climatically driven poleward range expansions, with some evidence for equatorial range retractions. Predicting their response to future climate scenarios is critical to their conservation, but ecological models are based only on short-term observations. The fossil record provides the only empirical evidence for the long-term response of organisms under perturbed climate states. The palaeontological record from the Last Interglacial (LIG; 125 000 years ago), a time of global warming, suggests that reef corals experienced poleward range shifts and an equatorial decline relative to their modern distribution. However, this record is spatio-temporally biased, and existing methods cannot account for data absence. Here, we use ecological niche modelling to estimate reef corals' realized niche and LIG distribution, based on modern and fossil occurrences. We then make inferences about modelled habitability under two future climate change scenarios (RCP4.5 and RCP8.5). Reef coral ranges during the LIG were comparable to the present, with no prominent equatorial decrease in habitability. Reef corals are likely to experience poleward range expansion and large equatorial declines under RCP4.5 and RCP8.5. However, this range expansion is probably optimistic in the face of anthropogenic climate change. Incorporation of fossil data in niche models improves forecasts of biodiversity responses under global climatic change.

Ecological niche modelling does not support climatically-driven dinosaur diversity decline before the Cretaceous/Paleogene mass extinction.

In the lead-up to the Cretaceous/Paleogene mass extinction, dinosaur diversity is argued to have been either in long-term decline, or thriving until their sudden demise. The latest Cretaceous (Campanian-Maastrichtian [83-66 Ma]) of North America provides the best record to address this debate, but even here diversity reconstructions are biased by uneven sampling. Here we combine fossil occurrences with climatic and environmental modelling to quantify latest Cretaceous North American dinosaur habitat. Ecological niche modelling shows a Campanian-to-Maastrichtian habitability decrease in areas with present-day rock-outcrop. However, a continent-wide projection demonstrates habitat stability, or even a Campanian-to-Maastrichtian increase, that is not preserved. This reduction of the spatial sampling window resulted from formation of the proto-Rocky Mountains and sea-level regression. We suggest that Maastrichtian North American dinosaur diversity is therefore likely to be underestimated, with the apparent decline a product of sampling bias, and not due to a climatically-driven decrease in habitability as previously hypothesised.