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Purpose: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. Patients and Methods: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. Results: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. Conclusions: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients’ circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.

BRCA2 reversion mutation detected in cell-free circulating DNA from patient 16.

Purpose:A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.Patients and Methods:Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies.Results:Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy.Conclusions:A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

Supplementary Methodology.

Liquid biopsy time points.

Abstract Fissure eruptions initiate with magma ascending and spreading through cracks in the ground that can extend for kilometres at the surface. Eruptions eventually localise to form one or a few persistent conduits and ultimately an array of discrete cones or craters. We built a new experimental apparatus to investigate the influences of fissure shape and wall-rock temperature on localisation within a volcanic fissure, and the thermal feedbacks associated with variability of these parameters. Our artificial fissure, or “Artfish,” has a slot geometry with adjustable shape and wall temperature. We can simulate both starting variability in fissure geometry and wall temperature, as well as changes in these parameters during an experiment to replicate, for example, blockage by wall-rock collapse, widening by wall-rock erosion, and warming by adjacent intrusions. We use polyethylene glycol (PEG 600) for our analogue fluid. A variable-speed pump allows for a range of fluid injection and ascent rates. Initial tests showcase the capabilities of the model and the types of data that may be acquired. Additional key features achieved include a stable and planar injection system, fluid recycling, and the use of particle tracers for monitoring flow patterns and velocities. The thermal evolution of the fluid-wall interface is quantitatively measured with thermal sensors, and the change in state of the PEG provides a clear visual indication of flow behaviour and solidification progress recorded on video. The potential experiments that can be conducted with this highly versatile model are numerous and will be used to gain a better understanding of the thermal controls on flow localisation and conduit development. This will assist hazard modellers to assess controls on eruption evolution and potentially to forecast sites where an initial fissure eruption may focus.

ObjectivesTo determine how many persons with knee pain have subsequent pain resolution and what factors are associated with resolution, focusing especially on types of physical activity.MethodsUsing data from MOST, an NIH funded longitudinal cohort study of persons with or at risk of knee osteoarthritis, we studied participants who at baseline reported knee pain on most days at both a telephone interview and clinic visit. We defined pain resolution if at 30 and 60 month exams, they reported no knee pain on most days and compared these participants to those who reported persistent pain later. In logistic regression analyses, we examined the association of baseline risk factors including demographic factors, BMI, depressive symptoms, isokinetic quadriceps strength and both overall physical activity (using the PASE survey) and specific activities including walking, gardening, and different intensities of recreational activities with pain resolution.ResultsOf 1,304 participants with knee pain on most days at baseline, 265 (20.3%) reported no knee pain at 30 and 60 months. Lower BMI and stronger quadriceps were associated with higher odds of pain resolution while overall physical activity was not. Of activities, walking decreased the odds of pain resolution (adjOR=0.86 (95% CI 0.76, 0.98)), but gardening (adjOR=1.59 (1.16, 2.18)) and moderate intensity recreational activities ((adjOR=1.24 (1.05, 1.46)) increased it.ConclusionPain resolution is common in those with knee pain. Factors increasing the odds of pain resolution include lower BMI, greater quadriceps strength and gardening and moderately intensive recreational activities.

This study cross-validated the dot counting test (DCT) as a performance validity test (PVT) in an adult attention-deficit/hyperactivity disorder (ADHD) clinical population and examined the effect of ADHD subtype and psychiatric comorbidity on accuracy for detecting invalidity. DCT performance was assessed among 210 consecutive adult ADHD referrals who underwent neuropsychological evaluation and were classified into valid ( n = 175) or invalid ( n = 35) groups based on seven independent criterion PVTs. The invalid group had significantly worse DCT performance than the valid group using both the standard and unrounded scoring procedure ([Formula: see text]). Classification accuracy was excellent, with 54.3% sensitivity/92% specificity at optimal cut-scores of ≥14 (rounded) and ≥13.38 (unrounded). Nonsignificant DCT performance differences emerged based on ADHD subtype or the presence/absence of comorbid psychopathology. The DCT functions well as a nonmemory-based PVT in an ethnoracially diverse ADHD population, supporting its clinical utility for detecting invalid neurocognitive performance during ADHD evaluations.

Physical activity (PA) is recommended to mitigate the symptoms of osteoarthritis (OA); however, this modality remains an unfamiliar construct for many patients and clinicians. Moreover, there can be confusion over the nuanced differences in terminology, such as exercise, sedentary behavior, and moderate intensity. The purpose of this scoping review is to provide a basic overview of PA including terminology, summarize the importance of PA for adults with OA, and discuss current gaps in the literature. Broadly, PA is defined as any energy expenditure from skeletal muscle above a resting level, and exercise is considered a type of PA that is planned, structured, and repetitive. Robust literature shows that PA has a modest protective effect on pain, functional limitation, and disability for OA, in addition to positive effects on a broad range of outcomes from mood and affect to mortality and morbidity in the general population. We provide recommendations for which measurement instruments can be used to record PA, both from a clinical and research perspective, as well as which metrics to employ for summarizing daily activity.

ObjectiveTo determine the relationship of patellofemoral osteoarthritis (PFOA) to changes in performance-based function over 7 years.MethodsThere were 2666 participants (62.2 ± 8.0 yrs, BMI 30.6 ± 5.9 kg/m2, 60% female) from the Multicenter Osteoarthritis Study with knee radiographs at baseline who completed repeated chair stands and a 20-meter walk test (20MWT) at baseline, 2.5, 5, and 7 years. Generalized linear models assessed the relation of radiographic PFOA and radiographic PFOA with frequent knee pain to longitudinal changes in performance-based function. Analyses were adjusted for age, sex, BMI, tibiofemoral OA, and injury/surgery.ResultsLinear models demonstrated a significant group-by-time interaction for the repeated chair stands (P = 0.04) and the 20MWT (P < 0.0001). Those with radiographic PFOA took 1.01 seconds longer on the repeated chair stands (P = 0.02) and 1.69 seconds longer on the 20MWT (P < 0.0001) at 7 years compared with baseline. When examining the relation of radiographic PFOA with frequent knee pain to performance-based function, there was a significant group-by-time interaction for repeated chair stands (P = 0.05) and the 20MWT (P < 0.0001). Those with radiographic PFOA with frequent knee pain increased their time on the repeated chair stands by 1.12 seconds (P = 0.04) and on the 20MWT by 1.91 seconds (P < 0.0001) over 7 years.ConclusionIndividuals with radiographic PFOA and those with radiographic PFOA with frequent knee pain have worsening of performance-based function over time. This knowledge may present opportunities to plan for early treatment strategies for PFOA to limit functional decline over time.

The aim of the study was to investigate (1) trajectories of physical activity (PA) over 96 months and (2) study to what extent knee pain, muscle strength, physical function, and radiographic disease were associated with PA trajectories in adults with or at risk of knee osteoarthritis (KOA).Using the Osteoarthritis Initiative (OAI) database, we described PA trajectories with the Physical Activity Scale for the Elderly (PASE) over 96 months. Knee pain was categorized into three groups: "no pain" [visual numeric pain rating scale (VAS=0)], "little to some pain" (VAS=1-3), or "moderate to severe pain" (VAS ≥ 4). Knee extensor strength was classified into high [16.21 (men) and10.82 (women) N/kg/m2 ] and low [12 seconds) and fast (12 seconds) groups. Radiographic disease was classified as present [Kellgren-Lawrence (KL) ≥2] or absent (KL grade2) of KOA.Among 3755 participants (age 61.0 ± 9.0 years, body mass index 28.5±4.8 kg/m2 , 58% female), we identified three trajectories: sedentary PA with slow decline (44.3%), low PA with slow decline (41.3%), and high PA with slow decline (14.4%). Poorer gait speed (OR: 2.32; 95% CI: 1.71-3.16), chair stand time (OR: 1.45; 95% CI: 1.07-1.96), and knee extensor strength (OR: 1.35; 95% CI: 1.03-1.76), but not pain or radiographic disease, were associated with PA trajectory of sedentary PA with slow decline.Physical function and strength, but not pain and radiographic disease, were associated with a trajectory of decline in PA among adults with or at risk of KOA.

We provided an overview of narrative reviews, systematic reviews, and meta-analyses that summarize primary evidence of how physical activity (PA) relates to structural progression of knee osteoarthritis (OA). This overview can serve as a resource for healthcare providers when recommending PA to patients with, or at risk, for knee OA.We searched the PubMED database for publications on "exercise" [MeSH Terms] and "knee osteoarthritis" [MeSH Terms]. We restricted our search to review articles, originally published in English, from 2005 to 2020. We then added several original studies to provide more detailed support of the findings of the review articles, based on the authors familiarity with the literature.We summarized the findings of 20 reviews and an additional 12 original studies. We found consistent evidence that common forms of PA (walking, running, and certain recreational sports) are not related to structural progression of knee OA, and can be safely recommended to patients with, or at risk, for knee OA.Healthcare providers can refer to this overview of the evidence, as well as current PA guidelines, when recommending PA to their patients with, or at risk for, knee OA. Future studies can support PA guidelines that target preserving the structural integrity of the knees.

In the face of the current global extinction crisis, it is critical we give conservation management strategies the best chance of success. Australia is not exempt from global trends with currently the world’s greatest mammal extinction rate (~ 1 per 8 years). Many more are threatened including the dibbler (Parantechinus apicalis) whose remnant range has been restricted to Western Australia at just one mainland site and two small offshore islands—Whitlock Island (5 ha) and Boullanger Island (35 ha). Here, we used 14 microsatellite markers to quantify genetic variation in the remaining island populations from 2013 to 2018 and incorporated these data into population viability analysis (PVA) models, used to assess factors important to dibbler survival and to provide guidance for translocations. Remnant population genetic diversity was low (STs 0.29–0.52). Comparison of empirical data to an earlier study is consistent with recent declines in genetic diversity and models projected increasing extinction risk and declining genetic variation in the next century. Optimal translocation scenarios recommend 80 founders for new dibbler populations—provided by captive breeding—and determined the proportion of founders from parental populations to maximise genetic diversity and minimise harvesting impact. The goal of our approach is long-term survival of genetically diverse, self-sustaining populations and our methods are transferable. We consider mixing island with mainland dibblers to reinforce genetic variation.

Previous research suggests individuals with intellectual disabilities (ID) may experience autonomic dysfunction, however, this has not been thoroughly investigated. The aim of this study was to compare the autonomic response to standing up (active orthostasis) and head-up tilt (passive orthostasis) in individuals with ID to a control group without ID. Eighteen individuals with and 18 individuals without ID were instrumented with an ECG-lead and finger-photoplethysmography for continuous heart rate and blood pressure recordings. The active and passive orthostasis protocol consisted of 10-min supine rest, 10-min standing, 10-min supine recovery, 5-min head-up tilt at 70, followed by 10-min supine recovery. The last 5 min of each position was used to calculate hemodynamic and autonomic function (time- and frequency-domain heart rate and blood pressure variability measures and baroreflex sensitivity). Individuals with ID had higher heart rate during baseline and recovery (P < 0.05), and an attenuated hemodynamic (stroke volume, heart rate) and heart rate variability response to active and passive orthostasis (interaction effect P < 0.05) compared with individuals without ID. Mean arterial pressure (MAP) was higher in individuals with ID at all timepoints. Individuals with ID demonstrated altered hemodynamic and autonomic regulation compared with a sex- and age-matched control group, evidenced by a higher mean arterial pressure and a reduced response in parasympathetic modulation to active and passive orthostasis. NEW & NOTEWORTHY Individuals with ID demonstrated altered hemodynamic and autonomic regulation to the clinical autonomic function tasks standing up and head-up tilt (active and passive orthostasis). Higher resting heart rate and higher MAP throughout the protocol suggest a higher arousal level, and individuals with ID showed a blunted response in parasympathetic modulation. Further research should investigate the relationship of these findings with clinical outcomes.

This study investigated the relationship between symptom validity scales on the Clinical Assessment of Attention Deficit-Adult (CAT-A) and the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in the context of Attention-Deficit/Hyperactivity Disorder (ADHD) evaluation. The sample comprised 140 consecutive patients referred for a neuropsychological evaluation of ADHD and were administered the CAT-A and the MMPI-2-RF and a battery of performance-based neurocognitive tests. Results indicated CAT-A/MMPI-2-RF symptom validity concordance of 51% between measures, with 38% concordant valid and 13% concordant invalid responses. Among those with discordance symptom validity results, rates of valid CAT-A/invalid MMPI-2-RF responding (41%) were more common than invalid CAT-A/valid MMPI-2-RF responding (8%). Results also indicated higher levels of ADHD symptoms among invalid responding within the CAT-A, whereas the MMPI-2-RF Cognitive Complaints scale did not differ by CAT-A validity status. Finally, symptom validity scales on both the CAT-A and MMPI-2-RF were largely discordant from neuropsychological test validity status per performance validity tests. Findings highlight the need for symptom validity testing when assessing ADHD and indicate that validity indices on broad personality assessments may assess different constructs than embedded validity indices in ADHD-specific measures.

ObjectiveTo examine the joint association of moderate-to-vigorous intensity physical activity (MVPA) and sedentary behavior with the risk of developing functional limitation 4 years later in adults with knee osteoarthritis (OA).MethodsUsing 48-month (baseline) accelerometry data from the Osteoarthritis Initiative, we classified participants as Active-Low Sedentary (≥ 1 10-min bout/week of MVPA, lowest tertile for standardized sedentary time), Active-High Sedentary (≥ 1 10-min bout/week of MVPA, top 2 tertiles for standardized sedentary time), Inactive-Low Sedentary (zero 10-min bouts/week of MVPA, lowest tertile for standardized sedentary time), and Inactive-High Sedentary (zero 10-minute bouts/week of MVPA, top 2 tertiles for standardized sedentary time) groups. Functional limitation was defined as > 12 seconds for the 5-repetition sit-to-stand test (5XSST) and < 1.22 m/s gait speed during the 20-meter walk test. To investigate the association of exposure groups with risk of developing functional limitation 4 years later, we calculated adjusted risk ratios (aRR; adjusted for potential confounders).ResultsOf 1091 and 1133 participants without baseline functional limitation, based on the 5XSST and 20-meter walk test, respectively, 15% and 21% developed functional limitation 4 years later. The Inactive-Low Sedentary and Inactive-High Sedentary groups had increased risk of developing functional limitations compared to the Active-Low Sedentary and Active-High Sedentary groups. The Inactive-Low Sedentary group had 72% (aRR 1.72, 95% CI 1.00–2.94) and 52% (aRR 1.52, 95% CI 1.03–2.25) more risk of developing functional limitation based on the 5XSST and 20-meter walk test, respectively, compared to the Active-Low Sedentary group.ConclusionRegardless of sedentary category, being inactive (zero 10-min bouts/week in MVPA) may increase the risk of developing functional limitation in adults with knee OA.

Knee replacement (KR) rates are increasing exponentially in the US and straining insurance budgets. This study was undertaken to investigate how many KRs would be prevented at different levels of pain improvement, a major target of osteoarthritis (OA) trials.We used data from the Osteoarthritis Initiative (OAI) to emulate a trial of knee pain interventions on KR risk changes. We modeled hypothetical 1-, 2- or 3-unit reductions of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale whenever a person reported a pain score of ≥5 (of 20) in an affected knee at any clinic visit. We used causal inference-based targeted learning to estimate treatment effects for hypothesized pain intervention strategies adjusted for time-dependent confounding. Sensitivity analyses assessed interventions at WOMAC pain scores of ≥4 and ≥7.Of the 9,592 knees studied (n = 4,796 participants; 58.5% female; baseline age 61.2 years), 40.7% experienced WOMAC pain scores of ≥5. The estimated knee-level (reference) risk of a KR, adjusted for loss to follow-up and death, was 6.3% (95% confidence interval 5.0, 7.7%) in the OAI. Reductions of WOMAC pain scores by 1, 2, or 3 units decreased the KR risk from 6.3% to 5.8%, 5.3%, and 4.9%, respectively. Larger reductions in KR risk were achieved when interventions were applied at a WOMAC pain score of ≥4.Modest pain reductions from OA interventions would substantially reduce the number of KRs, with greater reductions achieved when pain decreased more and when interventions were introduced at lower pain levels.