Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

AIM: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study. MATERIALS AND METHODS: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW). RESULTS: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death. CONCLUSIONS: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.

Computing and interpreting the Number Needed to Treat for Cardiovascular Outcomes Trials : Perspective on GLP-1 RA and SGLT-2i therapies.

The recent results of Cardiovascular Outcomes Trials (CVOTs) in type 2 diabetes have clearly established the cardiovascular (CV) safety or even the benefit of two therapeutic classes, Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Co-Transporter-2 inhibitors (SGLT-2i). Publication of the latest CVOTs for these therapeutic classes also led to an update of ESC guidelines and ADA/EASD consensus report in 2019, which considers using GLP-1 RA or SGLT-2i with proven cardiovascular benefit early in the management of type 2 diabetic patient with established cardiovascular disease (CVD) or at high risk of atherosclerotic CVD. The main beneficial results of these time-to event studies are supported by conventional statistical measures attesting the effectiveness of GLP-1 RA or SGLT2i on cardiovascular events (absolute risk, absolute risk difference, relative risk, relative risk reduction, odds ratio, hazard ratio). In addition, another measure whose clinical meaning appears to be easier, the Number Needed to Treat (NNT), is often mentioned while discussing the results of CVOTs, in order to estimating the clinical utility of each drug or sometimes trying to establish a power ranking. While the value of the measure is admittedly of interest, the subtleties of its computation in time-to-event studies are little known. We provide in this article a clear and practical explanation on NNT computation methods that should be used in order to estimate its value, according to the type of study design and variables available to describe the event of interest, in any randomized controlled trial. More specifically, a focus is made on time-to-event studies of which CVOTs are part, first to describe in detail an appropriate and adjusted method of NNT computation and second to help properly interpreting NNTs with the example of CVOTs conducted with GLP-1 RA and SGLT-2i. We particularly discuss the risk of misunderstanding of NNT values in CVOTs when some specific parameters inherent in each study are not taken into account, and the following risk of erroneous comparison between NNTs across studies. The present paper highlights the importance of understanding rightfully NNTs from CVOTs and their clinical impact to get the full picture of a drug's effectiveness.

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

BACKGROUND: There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE). MATERIALS AND METHODS: Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy. RESULTS: Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P = .28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P = .14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P = .60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this. CONCLUSION: In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients.

Cardiovascular Profile of Patients with Type 2 Diabetes in France Based on REWIND CVOT Inclusion Criteria: A Real-World Retrospective Study.

INTRODUCTION: The REWIND study demonstrated a cardiovascular (CV) benefit of dulaglutide treatment in patients with type 2 diabetes (T2D) with or without established cardiovascular disease (CVD). The current study aims to describe similarities and differences between characteristics of patients with T2D in France and the REWIND population. METHODS: A retrospective, observational study was conducted in France using primary care IQVIA electronic medical records. Patients aged ≥ 18 years with at least one clinical visit and/or glucose-lowering agent prescription in 2019 were identified. The percentages of patients aged ≥ 50 years with established CVD, aged ≥ 55 years with subclinical CVD or aged ≥ 60 years with multiple CV risk factors based on REWIND definitions were calculated. RESULTS: A total of 63,927 patients with T2D were included. Mean age was 67 years, 93% were aged ≥ 50 years and 58% were male. The median time since T2D diagnosis was 5.6 years, mean glycated hemoglobin was 7.1% and mean body mass index was 30.4 kg/m2. Of the patients included in the current study, 59.4% fulfilled REWIND CV criteria; 12.4% of patients were ≥ 50 years old with established CVD; 9.7% of patients were aged ≥ 55 years with subclinical vascular disease and 44.7% were aged ≥ 60 years with ≥ 2 CV risk factors. CONCLUSION: Almost 60% of this primary care French cohort with T2D fulfilled key REWIND CV criteria, with a lower percentage of patients having established CVD than REWIND participants.

Optimizing Earthquake Nowcasting With Machine Learning: The Role of Strain Hardening in the Earthquake Cycle.

Nowcasting is a term originating from economics, finance, and meteorology. It refers to the process of determining the uncertain state of the economy, markets or the weather at the current time by indirect means. In this paper, we describe a simple two-parameter data analysis that reveals hidden order in otherwise seemingly chaotic earthquake seismicity. One of these parameters relates to a mechanism of seismic quiescence arising from the physics of strain-hardening of the crust prior to major events. We observe an earthquake cycle associated with major earthquakes in California, similar to what has long been postulated. An estimate of the earthquake hazard revealed by this state variable time series can be optimized by the use of machine learning in the form of the Receiver Operating Characteristic skill score. The ROC skill is used here as a loss function in a supervised learning mode. Our analysis is conducted in the region of 5° × 5° in latitude-longitude centered on Los Angeles, a region which we used in previous papers to build similar time series using more involved methods (Rundle & Donnellan, 2020, https://doi.org/10.1029/2020EA001097; Rundle, Donnellan et al., 2021, https://doi.org/10.1029/2021EA001757; Rundle, Stein et al., 2021, https://doi.org/10.1088/1361-6633/abf893). Here we show that not only does the state variable time series have forecast skill, the associated spatial probability densities have skill as well. In addition, use of the standard ROC and Precision (PPV) metrics allow probabilities of current earthquake hazard to be defined in a simple, straightforward, and rigorous way.

Improving access to geodetic imaging crustal deformation data using GeoGateway.

GeoGateway (http://geo-gateway.org) is a web-based interface for analysis and modeling of geodetic imaging data and to support response to related disasters. Geodetic imaging data product currently supported by GeoGateway include Global Navigation Satellite System (GNSS) daily position time series and derived velocities and displacements and airborne Interferometric Synthetic Aperture Radar (InSAR) from NASA's UAVSAR platform. GeoGateway allows users to layer data products in a web map interface and extract information from various tools. Extracted products can be downloaded for further analysis. GeoGateway includes overlays of California fault traces, seismicity from user selected search parameters, and user supplied map files. GeoGateway also provides earthquake nowcasts and hazard maps as well as products created for related response to natural disasters. A user guide is present in the GeoGateway interface. The GeoGateway development team is also growing the user base through workshops, webinars, and video tutorials. GeoGateway is used in the classroom and for research by experts and non-experts including by students.

The Impact of COVID-19 Lockdown on Metabolic Control and Access to Healthcare in People with Diabetes: the CONFI-DIAB Cross-Sectional Study.

INTRODUCTION: The COVID-19 pandemic led to an international health crisis and restrictions. While the phenotype associated with COVID-19 severity in people with diabetes has rapidly been explored, the impact of restrictive measures, including lockdown, and tertiary care disruption on metabolic control and access to healthcare remained unknown. The aim of our study was to provide a comprehensive assessment on the overall management of diabetes during lockdown, including glucose control, weight changes, health care consumption and use of alternative forms of care such as telemedicine services, in a large sample of patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). METHODS: A prioritization of a care self-administered questionnaire was sent at the end of the first COVID-19 lockdown to all patients with diabetes routinely followed by diabetologists from the University Hospital of Nancy (France). This observational cross-sectional single-center study focused on data from patients with diabetes who returned the questionnaire along with medical records. The primary outcome was the change in HbA1c levels between the 6 months preceding and the 6 weeks following the lockdown. Data are expressed as numbers (%) or medians (quartiles). This study is registered with ClinicalTrials.gov (NCT04485351). RESULTS: We analyzed data from 870 patients with diabetes: 549 T2DM (63.1%), 520 males (59.8%), age 65.0 (57.0, 72.0), body mass index 28.6 (25.1, 32.9) and diabetes duration 20.0 (10.0, 30.0) years. HbA1c levels pre- and post-lockdown were respectively 7.7% (7.1, 8.4) and 7.4% (6.8, 8.2), translating into a significant reduction of - 0.1% (- 0.6, 0.15) (p < 0.0001). Stratified analyses suggested a consistent significant reduction of HbA1c independently of diabetes type. HbA1c reduction was significantly different according to weight changes: - 0.3% (- 0.8, 0.0), - 0.1% (- 0.5, 0.1) and - 0.1% (- 0.5, 0.3) for patients who lost, had stable or gained weight, respectively (p = 0.0029). Respectively, 423 (49.4%) and 790 (92.3%) patients did not consult their general practitioner and diabetologist. Blood tests were undergone by 379 (44.8%) patients, 673 (78.3%) did refill their prescriptions, and 269 (32.1%) used teleconsultation services. CONCLUSIONS: Despite the implementation of a lockdown and disruption in healthcare, no deterioration, rather an improvement, in metabolic control was observed in a large sample of patients with T1DM and T2DM.

Buried Aseismic Slip and Off-Fault Deformation on the Southernmost San Andreas Fault Triggered by the 2010 El Mayor Cucapah Earthquake Revealed by UAVSAR.

We use UAVSAR interferograms to characterize fault slip, triggered by the Mw 7.2 El Mayor-Cucapah earthquake on the 1 San Andreas Fault in the Coachella Valley providing comprehensive maps of short-term geodetic surface deformation that complement in situ measurements. Creepmeters and geological mapping of fault offsets on Durmid Hill recorded 4 and 8 mm of average triggered slip respectively on the fault, in contrast to radar views that reveal significant off-fault dextral deformation averaging 20 mm. Unlike slip in previous triggered slip events on the southernmost San Andreas fault, dextral shear in 2010 is not confined to transpressional hills in the Coachella valley. Edge detection and gradient estimation applied to the 50-m-sampled interferogram data identify the location (to 20 m) and local strike (to <4°) of secondary surface ruptures. Transverse curve fitting applied to these local detections provides local estimates of the radar-projected dextral slip and a parameter indicating the transverse width of the slip, which we equate with the depth of subsurface shear. These estimates are partially validated by fault-transverse interferogram profiles generated using the GeoGateway UAVSAR tool, and appear consistent for radar-projected slip greater than about 5 mm. An unexpected finding is that creep and triggered slip on the San Andreas fault terminate in the shallow subsurface below a surface shear zone that resists the simple expression of aseismic fault slip. We introduce the notion of a surface locking depth above which fault slip is manifest as distributed shear, and evaluate its depth as 6-27 m.

Clustering Analysis Methods for GNSS Observations: A Data-Driven Approach to Identifying California's Major Faults.

We present a data-driven approach to clustering or grouping Global Navigation Satellite System (GNSS) stations according to observed velocities, displacements or other selected characteristics. Clustering GNSS stations provides useful scientific information, and is a necessary initial step in other analysis, such as detecting aseismic transient signals (Granat et al., 2013, https://doi.org/10.1785/0220130039). Desired features of the data can be selected for clustering, including some subset of displacement or velocity components, uncertainty estimates, station location, and other relevant information. Based on those selections, the clustering procedure autonomously groups the GNSS stations according to a selected clustering method. We have implemented this approach as a Python application, allowing us to draw upon the full range of open source clustering methods available in Python's scikit-learn package (Pedregosa et al., 2011, https://doi.org/10.5555/1953048.2078195). The application returns the stations labeled by group as a table and color coded KML file and is designed to work with the GNSS information available from GeoGateway (Donnellan et al., 2021, https://doi.org/10.1007/s12145-020-00561-7; Heflin et al., 2020, https://doi.org/10.1029/2019ea000644) but is easily extensible. We demonstrate the methodology on California and western Nevada. The results show partitions that follow faults or geologic boundaries, including for recent large earthquakes and post-seismic motion. The San Andreas fault system is most prominent, reflecting Pacific-North American plate boundary motion. Deformation reflected as class boundaries is distributed north and south of the central California creeping section. For most models a cluster boundary connects the southernmost San Andreas fault with the Eastern California Shear Zone (ECSZ) rather than continuing through the San Gorgonio Pass.

HOW WELL DO OUTPATIENT PRESCRIPTIONS ADHERE TO GOOD ANTIMICROBIAL STEWARDSHIP?

AIM: Aims of the study included evaluation of outpatient antibiotic prescribing practices relating to good Antimicrobial Stewardship1 focusing on documentation of indication and duration. METHOD: Prescriptions dispensed at the Outpatient Pharmacy over a 6 week were evaluated. Data collected include patient's hospital identification in full, the antibiotic prescribed, duration of treatment, indication (in a specifically allocated area on the prescription) and route of administration, prescriber speciality and grade. Data were entered onto Microsoft Excel and reviewed by a committee that included a medical microbiologist and antimicrobial pharmacist. RESULTS: Five hundred and six antimicrobial prescriptions were reviewed. Therapeutic antibiotics accounted for 484/506 (95.6%) and the remaining 22/506 (4.4%) were prophylactic therapy. Indications were documented in 186/506 (36.8%) cases and 465/506 (91.9%) documented duration of therapy. By speciality, adherence with indication and duration, respectively, for oral medication, were as follows: Haematology 2/55 (3.6%) and 12/55 (21.8%), General paediatrics 26/42 (61.9%) and 41/42 (97.6%), Oncology 4/37 (10.8%) and 34/37 (91.9%), Dermatology 12/35 (34.3%) and 35/35 (100%), Nephrology 24/30 (80%) and 30/30 (100%), Ear Nose and Throat (ENT) 9/31 (29%) and 31/31 (100%). Oral route of administration was the most frequently prescribed 391/506 (77.3%), with topical and eye/ear drops prescribed in 63/506 (12.4%) and 50/506 (9.9%) respectively. Nebulised therapy accounted for only 2/506 (0.4%) prescriptions. Most commonly prescribed antibiotics were Co-amoxiclav 83/391 (21.2%), Flucloxacillin 50/391 (12.8%), Penicillin 35/391 (9.0%), Azithromycin 27/391 (6.9%) and Trimethoprim 26/391 (6.6%). Adherence to antibiotic guidelines was seen to be appropriate with 496/506 (98%).From the ten prescriptions that did not adhere, Azithromycin accounted for 8/10 (80%) with 50% of these used for prophylaxis, with lack of clear documentation. CONCLUSION: A designated area on the Outpatient Pharmacy prescription for indication and duration can aid better Antimicrobial Stewardship. Duration of therapy was better documented than indication, however it is postulated that this was to ensure adequate supply on outpatient dispensing and not always through following good antimicrobial prescribing practice. On the whole, the most commonly prescribed antibiotics were predominantly prescribed by the specialities within the antibiotic guidelines. Azithromycin, which is restricted to respiratory team, was prescribed outside of the policy by other specialties. This study helped prioritise which specialities require further input to improve adherence with Antimicrobial Stewardship in the outpatient setting. As dermatology and ENT had 100% compliance with specifying duration, we are now reviewing their prescribing education which can be used to enhance the practice of the other specialities.

Potential for a large earthquake near Los Angeles inferred from the 2014 La Habra earthquake.

Tectonic motion across the Los Angeles region is distributed across an intricate network of strike-slip and thrust faults that will be released in destructive earthquakes similar to or larger than the 1933 M6.4 Long Beach and 1994 M6.7 Northridge events. Here we show that Los Angeles regional thrust, strike-slip, and oblique faults are connected and move concurrently with measurable surface deformation, even in moderate magnitude earthquakes, as part of a fault system that accommodates north-south shortening and westerly tectonic escape of northern Los Angeles. The 28 March 2014 M5.1 La Habra earthquake occurred on a northeast striking, northwest dipping left-lateral oblique thrust fault northeast of Los Angeles. We present crustal deformation observation spanning the earthquake showing that concurrent deformation occurred on several structures in the shallow crust. The seismic moment of the earthquake is 82% of the total geodetic moment released. Slip within the unconsolidated upper sedimentary layer may reflect shallow release of accumulated strain on still-locked deeper structures. A future M6.1-6.3 earthquake would account for the accumulated strain. Such an event could occur on any one or several of these faults, which may not have been identified by geologic surface mapping.

[Renovascular safety of bevacizumab in breast cancer patients. The prognostic value of hypertension and proteinuria]. / Tolérance rénovasculaire du bévacizumab dans le cancer du sein. Valeur pronostique de l'hypertension et de la proteinuria.

INTRODUCTION: The potential prognostic value of hypertension and proteinuria of anti-vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in breast cancer. The objectives of the MARS study were to assess the prevalence of proteinuria and hypertension at baseline, their incidence under anti-VEGF treatment, and to evaluate a possible link with overall survival. METHODS: Patients from 8 centres were included between 2009 and 2011 with a follow-up of 1 year. They were naive of any previous anti-VEGF treatment and planned to be started on one. The results of the group of patients with breast cancer receiving bevacizumab are presented. RESULTS: Four hundred and two patients with breast cancer and treated with bevacizumab were included. At inclusion, hypertension prevalence was 12.4%, proteinuria 23.9%. The incidence of de novo proteinuria and hypertension during the follow-up was 61.7% and 16.8%, respectively. Among patients with de novo proteinuria, 62.2% afterwards improved/normalized. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria/hypertension were not associated with overall survival in breast cancer patients treated with bevacizumab. DISCUSSION: These results on the renovascular safety of bevacizumab in breast cancer patients showed that the prevalence of hypertension and proteinuria was high at baseline and, moreover, patients treated with bevacizumab frequently developed de novo hypertension and/or proteinuria. Finally, neither hypertension, nor proteinuria, neither at baseline, nor de novo, were associated with overall survival in our cohort of "real-life'' patients

Slip in the 1857 and earlier large earthquakes along the Carrizo Plain, San Andreas Fault.

The moment magnitude (Mw) 7.9 Fort Tejon earthquake of 1857, with a approximately 350-kilometer-long surface rupture, was the most recent major earthquake along the south-central San Andreas Fault, California. Based on previous measurements of its surface slip distribution, rupture along the approximately 60-kilometer-long Carrizo segment was thought to control the recurrence of 1857-like earthquakes. New high-resolution topographic data show that the average slip along the Carrizo segment during the 1857 event was 5.3 +/- 1.4 meters, eliminating the core assumption for a linkage between Carrizo segment rupture and recurrence of major earthquakes along the south-central San Andreas Fault. Earthquake slip along the Carrizo segment may recur in earthquake clusters with cumulative slip of approximately 5 meters.

Climate-modulated channel incision and rupture history of the San Andreas Fault in the Carrizo Plain.

The spatial and temporal distribution of fault slip is a critical parameter in earthquake source models. Previous geomorphic and geologic studies of channel offset along the Carrizo section of the south central San Andreas Fault assumed that channels form more frequently than earthquakes occur and suggested that repeated large-slip earthquakes similar to the 1857 Fort Tejon earthquake illustrate typical fault behavior. We found that offset channels in the Carrizo Plain incised less frequently than they were offset by earthquakes. Channels have been offset by successive earthquakes with variable slip since ~1400. This nonuniform slip history reveals a more complex rupture history than previously assumed for the structurally simplest section of the San Andreas Fault.