Ultra-Wide-Field Fluorescein Angiography Assessment of Non-Perfusion in Patients with Diabetic Retinopathy Treated with Anti-Vascular Endothelial Growth Factor Therapy.

Purpose: To follow the evolution of peripheral ischemia by fluorescein angiography (FA) on ultra-wide-field (UWF) images in diabetic patients treated with anti-vascular endothelial growth factor (anti-VEGF) for macular edema. Methods: Prospective, non-interventional cohort study analyzing UWF-FA images of 48 patients with diabetic retinopathy (48 eyes) treated for diabetic macular edema. UWF-FA was performed at baseline and after one year of anti-VEGF therapy (M12). The primary endpoint was the change in the non-perfusion index. Results: Of the 48 patients included in this study, 25 completed the one-year follow-up, and 20 had FA images of sufficient quality to be interpreted. The non-perfusion index did not significantly change from baseline after one year of anti-VEGF treatment (0.7% of the non-perfused area at baseline versus 0.5% at M12; p = 0.29). In contrast, the diabetic retinopathy severity score improved significantly between baseline and M12. Conclusions: Anti-VEGF treatment with aflibercept for diabetic macular edema had no impact on the retinal perfusion assessed by FA, but it allowed for artificially improving diabetic retinopathy severity scores.

Patients' Perceived Importance of Medication and Adherence in Polypharmacy, a Quantitative, Cross-Sectional Study Using a Questionnaire Administered in Three Doctors' Private Practices in France.

BACKGROUND: Among the determinants of nonadherence, polypharmacy (common in people with multiple pathologies and especially in elderly patients), plays a major role. OBJECTIVE: In patients who are subject to polypharmacy involving different classes of medications, the first aim is to assess the impact of medication importance given by patients on (i) medication adherence and (ii) the respective effect of intentionality and habit in medication importance and medication adherence. The second objective is to compare the importance given to medication and adherence in the different therapeutic classes. PATIENTS AND METHODS: Patients taking 5-10 different medications for at least 1 month were included in a cross-sectional survey in three private practices in one region in France. RESULTS: This study included 130 patients (59.2 % female) with 851 medications in total. The mean ± standard deviation (SD) age was 70.5 ± 12.2 years. The mean ± SD of medications taken was 6.9 ± 1.7. Treatment adherence had a strong positive correlation with the patient-perceived medication importance (p < 0.001). Counter-intuitively, taking a large number of medications (≥7) was associated with being fully adherent (p = 0.02). A high intentional nonadherence score was negatively associated with high medication importance (p = 0.003). Furthermore, patient-perceived medication importance was positively associated with taking treatment by habit (p = 0.03). Overall nonadherence more strongly correlated with unintentional nonadherence (p < 0.001) than with intentional nonadherence (p = 0.02). Compared to the antihypertensive class, a decrease in adherence by medication was observed in psychoanaleptics (p < 0.0001) and drugs used in diabetes class (p = 0.002), and a decrease in importance in lipid-modifying agents class (p = 0.001) and psychoanaleptics (p < 0.0001). CONCLUSION: The perception of the importance of a medicine is associated with the place of intentionality and habit in patient adherence. Therefore, explaining the importance of a medicine should become an important part of patient education.

Fragility index of positive phase II and III randomised clinical trials of treatments for hepatocellular carcinoma (2002-2022).

Background & Aims: The fragility index (FI), i.e., theminimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant, is a metric to evaluate the robustness of randomized controlled trials (RCTs). We aimed to assess the FI in the field of HCC. Methods: This is a retrospective analysis of phase 2 and 3 RCTs for the treatment of HCC published between 2002 and 2022. We included two-arm studies with 1:1 randomization and significant positive results for a primary time-to-event endpoint for the FI calculation, which involves the iterative addition of a best survivor from the experimental group to the control group, until positive significance (p <0,05, Log-rank test) is lost. Results: We identified 51 phase 2 and 3 positive RCTs, of which 29 (57%) were eligible for fragility index calculation. After reconstruction of the Kaplan-Meier curves, 25/29 studies remained significant, among which the analysis was performed. The median (interquartile range (IQR)) FI was 5 (2-10) and Fragility Quotient (FQ) was 3% (1%-6%). Ten trials (40%) had a FI of 2 or less. FI was positively correlated to the blind assessment of the primary endpoint (median FI 9 with blind assessment versus 2 without, p = 0.01), the number of reported events in the control arm (RS = 0.45, p = 0.02) and to impact factor (RS = 0.58, p = 0.003). Conclusions: Several phases 2 and 3 RCTs in HCC have a low fragility index, underlying the limited robustness on the conclusion of their superiority over control treatments. The fragility index might provide an additional tool to assess the robustness of clinical trial data in HCC. Impact and implications: The fragility index is a method to assess robustness of a clinical trial and is defined the minimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant. Among 25 randomised controlled trials in HCC, the median fragility index was 5, and 10 trials among 25 (40%) had a fragility index of 2 or less, indicating an important fragility.

Ambulatory Glucose Profile According to Different Phases of the Menstrual Cycle in Women Living With Type 1 Diabetes.

CONTEXT: Some women living with type 1 diabetes complain of changes in glucose values according to the different phases of menstruation. OBJECTIVE: To evaluate this variability through continuous glucose monitoring (CGM) data in type 1 diabetes patients. DESIGN: Observational study. SETTING: Ambulatory data, recruitment in 2 centers in the Paris region. PATIENTS: Twenty-four women with type 1 diabetes having spontaneous menstrual cycles. INTERVENTION: Collection of CGM data for 62 spontaneous menstrual cycles, with evaluation of five 3-day phases during each cycle: (1) early follicular (menstruations), (2) mid-follicular, (3) peri-ovulatory, (4) mid-luteal, and (5) late luteal. MAIN OUTCOME MEASURE: Time in range (TIR, prespecified). RESULTS: TIR decreased for each consecutive phase (61 ±â€…18%; 59 ±â€…18%; 59 ±â€…20%; 57 ±â€…18%; and 55 ±â€…20%, P = 0.02). The linear mixed model highlighted a decrease in TIR in the mid-luteal (P = 0.03) and late luteal (P < 0.001) phases compared with the early follicular phase. Time above range was significantly higher during the late luteal phase than the early follicular phase (P = 0.003). Time below range was significantly higher during the mid-follicular phase than in the early follicular phase. CONCLUSION: In most of the study population, glucose levels rose linearly throughout the menstrual cycle, reaching a maximum in the late luteal phase. A sharp decrease was seen for most participants at the beginning of menstrual bleeding. This should be taken into consideration in daily care of type 1 diabetes patients to avoid hypoglycemia.

Humoral response to mRNA anti-COVID-19 vaccines BNT162b2 and mRNA-1273 in patients with chronic lymphocytic leukemia.

Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.

Stratification in systemic sclerosis according to autoantibody status versus skin involvement: a study of the prospective EUSTAR cohort.

BACKGROUND: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. METHODS: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. FINDINGS: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81-0·84 for cutaneous only vs 0·84, 0·82-0·85 for antibody only vs 0·84, 0·83-0·86 for combined) or for progression-free survival (0·70, 0·69-0·71 vs 0·71, 0·70-0·72 vs 0·71, 0·70-0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46-0·71 for antibody only vs 0·29, 0·19-0·39 for cutaneous only) and disease progression (0·36, 0·29-0·46 vs 0·21, 0·14-0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70-0·74 for antibody only vs 0·66, 0·64-0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75-0·77 vs 0·71, 0·70-0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. INTERPRETATION: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. FUNDING: World Scleroderma Foundation.

A short course of corticosteroids reduces the risk of mechanical ventilation and death in patients with moderate to severe COVID 19 pneumonia: results of a retrospective monocentric cohort.

BACKGROUND: Reduced mortality at 28 days in patients treated with corticosteroids was demonstrated, but this result was not confirmed by certain large epidemiological studies. Our aim was to determine whether corticosteroids improve the outcomes of our patients hospitalized with COVID-19 pneumonia. METHODS: Our retrospective, single centre cohort study included consecutive patients hospitalized for moderate to severe COVID-19 pneumonia between March 15 and April 15 2020. An early short course of corticosteroids was given during the second phase of the study. The primary composite endpoint was the need for mechanical ventilation or mortality within 28 days of admission. A multivariate logistic regression model was used to estimate the propensity score, i.e. the probability of each patient receiving corticosteroid therapy based on the initial variables. RESULTS: About 120 consecutive patients were included, 39 in the "corticosteroids group", 81 in the "no corticosteroids group"; their mean ages (±SD) were 66.4 ± 14.1 and 66.1 ± 15.2 years, respectively. Mechanical ventilation-free survival at 28 days was higher in the "corticosteroids group" than in the "no corticosteroids group" (71% and 29% of cases, respectively, p < .0001). The effect of corticosteroids was confirmed with HR .28 (95%CI .10-.79), p = .02. In older and comorbid patients who were not eligible for intensive care, the effect of corticosteroid therapy was also beneficial (HR .36 (95%CI .16-.80), p = .01). CONCLUSION: A short course of corticosteroids reduced the risks of death or mechanical ventilation in patients with moderate to severe COVID-19 pneumonia in all patients and also in older and comorbid patients not eligible for intensive care.

PD-1/PD-L1 expression in anal squamous intraepithelial lesions.

INTRODUCTION: Studies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively). MATERIALS AND METHODS: Patients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups. RESULTS: 33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, p = 0.01; and 62% vs. 33%, p = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, p = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells. CONCLUSIONS: Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.