Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the ‘standard’ treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL

Paleogeodetic records of seismic and aseismic subduction from central Sumatran microatolls, Indonesia

We utilize coral microatolls in western Sumatra to document vertical deformation associated with subduction. Microatolls are very sensitive to fluctuations in sea level and thus act as natural tide gauges. They record not only the magnitude of vertical deformation associated with earthquakes (paleoseismic data), but also continuously track the long-term aseismic deformation that occurs during the intervals between earthquakes (paleogeodetic data). This paper focuses on the twentieth century paleogeodetic history of the equatorial region. Our coral paleogeodetic record of the 1935 event reveals a classical example of deformations produced by seismic rupture of a shallow subduction interface. The site closest to the trench rose 90 cm, whereas sites further east sank by as much as 35 cm. Our model reproduces these paleogeodetic data with a 2.3 m slip event on the interface 88 to 125 km from the trench axis. Our coral paleogeodetic data reveal slow submergence during the decades before and after the event in the areas of coseismic emergence. Likewise, interseismic emergence occurred before and after the 1935 event in areas of coseismic submergence. Among the interesting phenomenon we have discovered in the coral record is evidence of a large aseismic slip or “silent event” in 1962, 27 years after the 1935 event. Paleogeodetic deformation rates in the decades before, after, and between the 1935 and 1962 events have varied both temporally and spatially. During the 25 years following the 1935 event, submergence rates were dramatically greater than in prior decades. During the past four decades, however, rates have been lower than in the preceding decades, but are still higher than they were prior to 1935. These paleogeodetic records enable us to model the kinematics of the subduction interface throughout the twentieth century

The value of recreational physical activity in Aotearoa New Zealand: A scoping review of evidence and implications for social value measurement

Internationally, there is rising interest in measuring the value of sport and physical activity to society. A critical step in valuing the sector is first establishing the relationship between engagement in sport and physical activity and the societal outcomes that ensue. This paper summarises the findings of a literature review carried out as part of a larger study on the Social Return on Investment (SROI) of recreational physical activity in Aotearoa New Zealand. The review aimed to synthesise existing evidence on the relationship between recreational physical activity and wellbeing outcomes for all New Zealanders, including tangata whenua (Māori, who are Aotearoa New Zealand’s Indigenous population). The methodology took the format of a scoping review and included a series of searches for academic and grey literature, including literature concerning Māori that might have been overlooked in a traditional academic search. The findings are grouped into five outcome areas: physical health; subjective wellbeing; individual development; personal behaviour; and social and community development. The review found some compelling evidence which shows examples of the links between sport and physical activity and outcomes in each of these areas for specific population sub-groups. In particular, for Māori, the findings demonstrate a strong impact on social and community development through building social capital and enhancing cultural identity. However, in all outcome areas, there is mixed quality evidence, a small amount of evidence on which to base definitive conclusions, and limited evidence relating to the monetary value of outcomes. The review concludes that there is a need for further research to strengthen the evidence base for social impact measurement, particularly around the impact of sport and physical activity for Indigenous populations

Semi-supervised learning towards automated segmentation of PET images with limited annotations: Application to lymphoma patients

The time-consuming task of manual segmentation challenges routine systematic quantification of disease burden. Convolutional neural networks (CNNs) hold significant promise to reliably identify locations and boundaries of tumors from PET scans. We aimed to leverage the need for annotated data via semi-supervised approaches, with application to PET images of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL). We analyzed 18F-FDG PET images of 292 patients with PMBCL (n=104) and DLBCL (n=188) (n=232 for training and validation, and n=60 for external testing). We employed FCM and MS losses for training a 3D U-Net with different levels of supervision: i) fully supervised methods with labeled FCM (LFCM) as well as Unified focal and Dice loss functions, ii) unsupervised methods with Robust FCM (RFCM) and Mumford-Shah (MS) loss functions, and iii) Semi-supervised methods based on FCM (RFCM+LFCM), as well as MS loss in combination with supervised Dice loss (MS+Dice). Unified loss function yielded higher Dice score (mean +/- standard deviation (SD)) (0.73 +/- 0.03; 95% CI, 0.67-0.8) compared to Dice loss (p-value<0.01). Semi-supervised (RFCM+alpha*LFCM) with alpha=0.3 showed the best performance, with a Dice score of 0.69 +/- 0.03 (95% CI, 0.45-0.77) outperforming (MS+alpha*Dice) for any supervision level (any alpha) (p<0.01). The best performer among (MS+alpha*Dice) semi-supervised approaches with alpha=0.2 showed a Dice score of 0.60 +/- 0.08 (95% CI, 0.44-0.76) compared to another supervision level in this semi-supervised approach (p<0.01). Semi-supervised learning via FCM loss (RFCM+alpha*LFCM) showed improved performance compared to supervised approaches. Considering the time-consuming nature of expert manual delineations and intra-observer variabilities, semi-supervised approaches have significant potential for automated segmentation workflows

Persistent elastic behavior above a megathrust rupture patch: Nias island, West Sumatra

We quantify fore-arc deformation using fossil reefs to test the assumption commonly made in seismic cycle models that anelastic deformation of the fore arc is negligible. Elevated coral microatolls, paleoreef flats, and chenier plains show that the Sumatran outer arc island of Nias has experienced a complex pattern of relatively slow long-term uplift and subsidence during the Holocene epoch. This same island rose up to 2.9 m during the Mw 8.7 Sunda megathrust rupture in 2005. The mismatch between the 2005 and Holocene uplift patterns, along with the overall low rates of Holocene deformation, reflects the dominance of elastic strain accumulation and release along this section of the Sunda outer arc high and the relatively subordinate role of upper plate deformation in accommodating long-term plate convergence. The fraction of 2005 uplift that will be retained permanently is generally <4% for sites that experienced more than 0.25 m of coseismic uplift. Average uplift rates since the mid-Holocene range from 1.5 to −0.2 mm/a and are highest on the eastern coast of Nias, where coseismic uplift was nearly zero in 2005. The pattern of long-term uplift and subsidence is consistent with slow deformation of Nias along closely spaced folds in the north and trenchward dipping back thrusts in the southeast. Low Holocene tectonic uplift rates provide for excellent geomorphic and stratigraphic preservation of the mid-Holocene relative sea level high, which was under way by ∼7.3 ka and persisted until ∼2 ka

Future Seismic Hazards in Southern California - Phase I: Implications of the 1992 Landers Earthquake Sequence

Southern California and its seismologists received a wake-up call on June 28, 1992. The largest earthquake to strike southern California in 40 years occurred near the town of Landers, located 30 km north of the San Andreas fault. It had a magnitude of 7.5 (M7.5). Three and one-half hours later, a M6.5 aftershock struck the Big Bear area 40 km (kilometers) to the west of Landers. An ad hoc working group was rapidly convened in July, 1992, to evaluate how the Landers-Big Bear earthquake sequence might affect future large earthquakes along major faults in southern California. In particular, what are the chances of large earthquakes in the next few years and how do they compare to previous estimates (such as those of the Working Group on California Earthquake Probabilities -- WGCEP, 1988)? Such an evaluation was made for central California after the Lorna Prieta earthquake of 1989 (WGCEP, 1990). The charge to the Landers ad hoc working group included analyzing the seismicity for the last several years in southern California and the new paleoseismic, geologic, and geodetic data recently available for southern California. To inform the public about the potential hazard of plausible earthquakes, the working group was also asked to map the predicted severity of ground shaking for such earthquakes compared to that from the Landers earthquake

Source parameters of the great Sumatran megathrust earthquakes of 1797 and 1833 inferred from coral microatolls

Large uplifts and tilts occurred on the Sumatran outer arc islands between 0.5° and 3.3°S during great historical earthquakes in 1797 and 1833, as judged from relative sea level changes recorded by annually banded coral heads. Coral data for these two earthquakes are most complete along a 160-km length of the Mentawai islands between 3.2° and 2°S. Uplift there was as great as 0.8 m in 1797 and 2.8 m in 1833. Uplift in 1797 extended 370 km, between 3.2° and 0.5°S. The pattern and magnitude of uplift imply megathrust ruptures corresponding to moment magnitudes (M_w) in the range 8.5 to 8.7. The region of uplift in 1833 ranges from 2° to at least 3.2°S and, judging from historical reports of shaking and tsunamis, perhaps as far as 5°S. The patterns and magnitude of uplift and tilt in 1833 are similar to those experienced farther north, between 0.5° and 3°N, during the giant Nias-Simeulue megathrust earthquake of 2005; the outer arc islands rose as much as 3 m and tilted toward the mainland. Elastic dislocation forward modeling of the coral data yields megathrust ruptures with moment magnitudes ranging from 8.6 to 8.9. Sparse accounts at Padang, along the mainland west coast at latitude 1°S, imply tsunami runups of at least 5 m in 1797 and 3–4 m in 1833. Tsunamis simulated from the pattern of coral uplift are roughly consistent with these reports. The tsunami modeling further indicates that the Indian Ocean tsunamis of both 1797 and 1833, unlike that of 2004, were directed mainly south of the Indian subcontinent. Between about 0.7° and 2.1°S, the lack of vintage 1797 and 1833 coral heads in the intertidal zone demonstrates that interseismic submergence has now nearly equals coseismic emergence that accompanied those earthquakes. The interseismic strains accumulated along this reach of the megathrust have thus approached or exceeded the levels relieved in 1797 and 1833

Psychological impact of working in paediatric intensive care. A UK-wide prevalence study

OBJECTIVE: To determine the prevalence of work-related psychological distress in staff working in UK paediatric intensive care units (PICU). DESIGN: Online (Qualtrics) staff questionnaire, conducted April to May 2018. SETTING: Staff working in 29 PICUs and 10 PICU transport services were invited to participate. PARTICIPANTS: 1656 staff completed the survey: 1194 nurses, 270 physicians and 192 others. 234 (14%) respondents were male. Median age was 35 (IQR 28-44). MAIN OUTCOME MEASURES: The Moral Distress Scale-Revised (MDS-R) was used to look at moral distress, the abbreviated Maslach Burnout Inventory to examine the depersonalisation and emotional exhaustion domains of burnout, and the Trauma Screening Questionnaire (TSQ) to assess risk of post-traumatic stress disorder (PTSD). RESULTS: 435/1194 (36%) nurses, 48/270 (18%) physicians and 19/192 (10%) other staff scored above the study threshold for moral distress (≥90 on MDS-R) (χ2 test, p<0.00001). 594/1194 (50%) nurses, 99/270 (37%) physicians and 86/192 (45%) other staff had high burnout scores (χ2 test, p=0.0004). 366/1194 (31%) nurses, 42/270 (16%) physicians and 21/192 (11%) other staff scored at risk for PTSD (χ2 test, p<0.00001). Junior nurses were at highest risk of moral distress and PTSD, and junior doctors of burnout. Larger unit size was associated with higher MDS-R, burnout and TSQ scores. CONCLUSIONS: These results suggest that UK PICU staff are experiencing work-related distress. Further studies are needed to understand causation and to develop strategies for prevention and treatment

Anaplastic large cell lymphoma, ALK-negative

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