Deep generative models for 3D molecular structure

Deep generative models have gained recent popularity for chemical design. Many of these models have historically operated in 2D space; however, more recently explicit 3D molecular generative models have become of interest, which are the topic of this article. Dozens of published models have been developed in the last few years to generate molecules directly in 3D, outputting both the atom types and coordinates, either in one-shot or adding atoms or fragments step-by-step. These 3D generative models can also be guided by structural information such as a binding pocket representation to successfully generate molecules with docking score ranges similar to known actives, but still showing lower computational efficiency and generation throughput than 1D/2D generative models and sometimes producing unrealistic conformations. We advocate for a unified benchmark of metrics to evaluate generation and propose perspectives to be addressed in next implementations.     

Long-Term Follow-up of Graves Orbitopathy After Treatment With Short- or Long-Term Methimazole or Radioactive Iodine

ObjectiveThe aim of this study was to compare long-term outcomes in terms of new onset or worsening of Graves orbitopathy (GO) in patients with Graves disease treated with different therapeutic modalities for hyperthyroidism.MethodsA total of 1163 patients with Graves disease were enrolled in this study; 263 patients were treated with radioiodine and 808 patients received methimazole (MMI) therapy for a median of 18 months, of whom 178 patients continued MMI for a total of 96 months (long-term methimazole [LT-MMI]). The thyroid hormonal status and GO were evaluated regularly for a median of 159 months since enrollment.ResultsThe rates of relapse, euthyroidism, and hypothyroidism at the end of follow-up were as follows: radioiodine treatment group: 16%, 22%, and 62%, respectively; short-term MMI group: 59%, 36%, and 5%, respectively; and LT-MMI group: 18%, 80%, and 2%, respectively. During the first 18 months of therapy, worsening of GO (11.5% vs 5.7%) and de novo development of GO (12.5% vs 9.8%) were significantly more frequent after radioiodine treatment (P <.004). Overall worsening and de novo development of GO from >18 to 234 months occurred in 26 (9.9%) patients in the radioiodine group and 8 (4.5%) patients in the LT-MMI group (P <.037). No case of worsening or new onset of GO was observed in patients treated with LT-MMI from >60 to 234 months of follow-up.ConclusionProgression and development of GO were associated more with radioiodine treatment than with MMI treatment; GO may appear de novo or worsen years after radioiodine treatment but not after LT-MMI therapy.     

Association Between Non-Alcoholic Fatty Liver Disease and Diabetes-Related Microvascular Complications: A Retrospective Cross-Sectional Study of Hospitalized Patients

ObjectiveOwing to limited research, the effect of nonalcoholic fatty liver disease (NAFLD) on type 2 diabetes outcomes remains unclear. This study aimed to investigate the association between NAFLD and microvascular complications in hospitalized patients with type 2 diabetes.MethodsWe included 1982 patients with type 2 diabetes. NAFLD was defined as hepatic steatosis detected by ultrasound without secondary causes of fat accumulation. The diagnosis of diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy was based on clinical medical records. Risk for advanced liver fibrosis was categorized as “low risk,” “indeterminate risk,” and “high risk,” based on the NAFLD fibrosis score (NAFLD-FS). Logistic regression was used to test the association between NAFLD, risk for advanced fibrosis, and the presence of DR, DKD, and diabetic neuropathy.ResultsThe prevalence of NAFLD was 61.3%. The presence of DR and DKD was inversely associated with NAFLD, after adjusting for covariates. The presence of DR and DKD was higher in the “indeterminate risk” and “high risk” groups than in the “low risk” group, after adjusting for the same covariates. Only the presence of DKD significantly increased with high NAFLD-FS.ConclusionThe presence of DR and DKD was inversely associated with NAFLD among hospitalized patients with type 2 diabetes. DKD was closely associated with high NAFLD-FS among patients with NAFLD.     

Projecting the future burden of cancer: Bayesian age–period–cohort analysis with integrated nested Laplace approximations

The projection of age‐stratified cancer incidence and mortality rates is of great interest due to demographic changes, but also therapeutical and diagnostic developments. Bayesian age–period–cohort (APC) models are well suited for the analysis of such data, but are not yet used in routine practice of epidemiologists. Reasons may include that Bayesian APC models have been criticized to produce too wide prediction intervals. Furthermore, the fitting of Bayesian APC models is usually done using Markov chain Monte Carlo (MCMC), which introduces complex convergence concerns and may be subject to additional technical problems. In this paper we address both concerns, developing efficient MCMC‐free software for routine use in epidemiological applications. We apply Bayesian APC models to annual lung cancer data for females in five different countries, previously analyzed in the literature. To assess the predictive quality, we omit the observations from the last 10 years and compare the projections with the actual observed data based on the absolute error and the continuous ranked probability score. Further, we assess calibration of the one‐step‐ahead predictive distributions. In our application, the probabilistic forecasts obtained by the Bayesian APC model are well calibrated and not too wide. A comparison to projections obtained by a generalized Lee–Carter model is also given. The methodology is implemented in the user‐friendly R‐package BAPC using integrated nested Laplace approximations.     

Longitudinal development of the cerebellum in human infants during the first 800 days

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Revisiting Cushing Syndrome,Milder Forms Are Now a Common Occurrence: A Single-Center Cohort of 76 Subjects

ObjectiveGuidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center.MethodsComputerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature.ResultsOf the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome.ConclusionsModern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed.