Evaluating cancer screening programs using survival analysis.

The main purpose of cancer screening programs is to provide early treatment to patients that are diagnosed with cancer on a screening test, thus increasing their chances of survival. To test this hypothesis directly, one should compare the survival of screen-detected cases to the survival of their counterparts not included to the program. In this study, we develop a general notation and use it to formally define the comparison of interest. We explain why the naive comparison between screen-detected and interval cases is biased and show that the total bias that arises in this case can be decomposed as a sum of lead time bias, length time bias, and bias due to overdetection. With respect to the estimation, we show what can be estimated using existing methods. To fill in the missing gap, we develop a new nonparametric estimator that allows us to estimate the survival of the control group, that is, the survival of cancer cases that would be screen-detected among those not included to the program. By joining the proposed estimator with existing methods, we show that the contrast of interest can be estimated without neglecting any of the biases. Our approach is illustrated using simulations and empirical data.

The Relative Preservation of the Central Retinal Layers in Leber Hereditary Optic Neuropathy.

(1) Background: The purpose of this study was to evaluate the thickness of retinal layers in Leber hereditary optic neuropathy (LHON) in the atrophic stage compared with presumably inherited bilateral optic neuropathy of unknown cause with the aim of seeing if any LHON-specific patterns exist. (2) Methods: 14 patients (24 eyes) with genetically confirmed LHON (LHON group) were compared with 13 patients (23 eyes) with negative genetic testing results (mtDNA + WES) and without identified etiology of bilateral optic atrophy (nonLHON group). Segmentation analysis of retinal layers in the macula and peripapillary RNFL (pRNFL) measurements was performed using Heidelberg Engineering Spectralis SD-OCT. (3) Results: In the LHON group, the thickness of ganglion cell complex (GCC) (retinal nerve fiber layer (RNFL)­ganglion cell layer (GCL)­inner plexiform layer (IPL)) in the central ETDRS (Early Treatment Diabetic Retinopathy Study) circle was significantly higher than in the nonLHON group (p < 0.001). In all other ETDRS fields, GCC was thinner in the LHON group. The peripapillary RNFL (pRNFL) was significantly thinner in the LHON group in the temporal superior region (p = 0.001). Longitudinal analysis of our cohort during the follow-up time showed a tendency of thickening of the RNFL, GCL, and IPL in the LHON group in the central circle, as well as a small recovery of the pRNFL in the temporal region, which corresponds to the observed central macular thickening. (4) Conclusions: In LHON, the retinal ganglion cell complex thickness (RNFL-GCL-IPL) appears to be relatively preserved in the central ETDRS circle compared to nonLHON optic neuropathies in the chronic phase. Our findings may represent novel biomarkers as well as a structural basis for possible recovery in some patients with LHON.

Is It Possible to Predict Clonal Thrombocytosis in Triple-Negative Patients with Isolated Thrombocytosis Based Only on Clinical or Blood Findings?

JAK2, MPL, and CALR mutations define clonal thrombocytosis in about 90% of patients with sustained isolated thrombocytosis. In the remainder of patients (triple-negative patients) diagnosing clonal thrombocytosis is especially difficult due to the different underlying conditions and possible inconclusive bone marrow biopsy results. The ability to predict patients with sustained isolated thrombocytosis with a potential clonal origin has a prognostic value and warrants further examination. The aim of our study was to define a non-invasive clinical or blood parameter that could help predict clonal thrombocytosis in triple-negative patients. We studied 237 JAK2 V617-negative patients who were diagnosed with isolated thrombocytosis and referred to the haematology service. Sixteen routine clinical and blood parameters were included in the logistic regression model which was used to predict the type of thrombocytosis (reactive/clonal). Platelet count and lactate dehydrogenase (LDH) were the only statistically significant predictors of clonal thrombocytosis. The platelet count threshold for the most accurate prediction of clonal or reactive thrombocytosis was 449 × 109/L. Other tested clinical and blood parameters were not statistically significant predictors of clonal thrombocytosis. The level of LDH was significantly higher in CALR-positive patients compared to CALR-negative patients. We did not identify any new clinical or blood parameters that could distinguish clonal from reactive thrombocytosis. When diagnosing clonal thrombocytosis triple-negative patients are most likely to be misdiagnosed. Treatment in patients with suspected triple negative clonal thrombocytosis should not be delayed if cardiovascular risk factors or pregnancy coexist, even in the absence of firm diagnostic criteria. In those cases the approach "better treat more than less" should be followed.

COVID-19 in Slovenia, from a Success Story to Disaster: What Lessons Can Be Learned?

During the first wave of the COVID-19 pandemic in spring 2020, Slovenia was among the least affected countries, but the situation became drastically worse during the second wave in autumn 2020 with high numbers of deaths per number of inhabitants, ranking Slovenia among the most affected countries. This was true even though strict non-pharmaceutical interventions (NPIs) to control the progression of the epidemic were being enforced. Using a semi-parametric Bayesian model developed for the purpose of this study, we explore if and how the changes in mobility, their timing and the activation of contact tracing can explain the differences in the epidemic progression of the two waves. To fit the model, we use data on daily numbers of deaths, patients in hospitals, intensive care units, etc., and allow transmission intensity to be affected by contact tracing and mobility (data obtained from Google Mobility Reports). Our results imply that though there is some heterogeneity not explained by mobility levels and contact tracing, implementing interventions at a similar stage as in the first wave would keep the death toll and the health system burden low in the second wave as well. On the other hand, sticking to the same timeline of interventions as observed in the second wave and focusing on enforcing a higher decrease in mobility would not be as beneficial. According to our model, the 'dance' strategy, i.e., first allowing the numbers to rise and then implementing strict interventions to make them drop again, has been played at too-late stages of the epidemic. In contrast, a 15-20% reduction of mobility compared to pre-COVID level, if started at the beginning and maintained for the entire duration of the second wave and coupled with contact tracing, could suffice to control the epidemic. A very important factor in this result is the presence of contact tracing; without it, the reduction in mobility needs to be substantially larger. The flexibility of our proposed model allows similar analyses to be conducted for other regions even with slightly different data sources for the progression of the epidemic; the extension to more than two waves is straightforward. The model could help policymakers worldwide to make better decisions in terms of the timing and severity of the adopted NPIs.

Prognostic Factor Analysis of Visual Outcome after Vitrectomy for Rhegmatogenous Retinal Detachment.

Pars plana vitrectomy (PPV) is a surgical approach mainly chosen for complex rhegmatogenous retinal detachment (RRD) repair with highly variable functional results. The aim of this analysis was to evaluate the impact of preoperative factors and postoperative optical coherence tomography (OCT) macular findings on the functional outcome of patients undergoing primary PPV for RRD. A retrospective analysis was performed on 88 eyes of 88 patients with complex RRD managed by PPV. A swept source OCT was used to obtain images at the postoperative visit at least 6 months after PPV. Hierarchical linear regression model was used to evaluate the influence of preoperative factors related to patient, ocular clinical and postoperative OCT macular findings on functional outcomes of PPV for RRD. Duration of symptoms (p = 0.031) and discontinuity of the ellipsoid zone (EZ) on OCT (p = 0.024) showed statistically significant negative correlation, while preoperative best-corrected visual acuity (BCVA; p < 0.001) showed statistically significant positive correlation to postoperative BCVA. Preoperative BCVA and duration of symptoms can be used as prognostic factors for visual outcome in patients undergoing PPV for RRD. Discontinuity of the EZ was the only postoperative OCT variable related to worse postoperative visual outcome.