Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Appraising the characteristics of particulate matter from leather tanning micro-environments, their respirational risks, and dysfunctions amid exposed working cohorts.

Leather tanneries are known for chemical laden work environments and pulmonic complaints among workers. This study presents an analysis of tannery micro-environments emphasizing on size-based variation in composition of particulate matter and consequent respiratory dysfunctions. Qualitative (FTIR, SEM-EDX) and quantitative assessment (elemental composition, carbon forms) of PM10 and 2.5 has been employed. For lung function evaluation of workforce, spirometry with ATS proprieties was used. The peak concentrations of both PM10 and 2.5 have been found at PU, FU, and B&S. The LTCR for only Cr is high for both PM2.5 and PM10. HQ was high for Al, Cr, and Mn for both PM sizes. The maximum organic and secondary organic carbon in PM10 was found at FU and in PM2.5 at PU. The varied PM composition included carbohydrate (B&S, WMO), ether (S&S, P&S) and hydroxyl (B&S, S&S, P&S), proteins, polyenes, vinyl groups (S&S, P&S, FU), alcohols (PU and FU), and aldehyde present at PU. These results were armored by high organic and total carbon concentrations for the same sites. Therefore, PM are classified into biogenic (carbonaceous: microbial and animal remains) from PU and WMO, incidental (industrial, mixt physico-chemical character) from PU, FU, WMO, B&S and P&S, and geogenic (crustal mineral dust) from RHT, B&S, PU, and P&S. Furthermore, increase in metal concentrations in PM10 (Cr, Mn, Co, Ni, V, As, Be, Ba, and Cd) and PM2.5 (As, Pb) while TC, OC, and SOC in PM2.5 caused depreciation overall lung function. The exposure to biogenic and incidental PM nature are key cause of pulmonic dysfunction.

A descriptive survey study in endocrinology clinic: evaluation of the use of natural products.

OBJECTIVE: The use of herbal products/dietary supplements (HP/DS) in endocrinal chronic diseases is growing. However, no studies have evaluated their use in patients who present to endocrinology and metabolic diseases clinics. This descriptive study aims to investigate the rate of HP/DS use and the factors affecting this in patients who presented to Karadeniz Technical University (KTU) Farabi Hospital Endocrinology and Metabolic Diseases Clinic, Türkiye between 01.11.2021 and 01.05.2022. METHODS: Five hundred six questionnaires with acceptable data quality were included this investigation. The data were analyzed on SPSS version 23.0 software. The factors with the greatest effect on the use of HP/DS were determined using binary logistic regression analysis. RESULTS: Analysis showed that 49.4% of the participants used HP/DS. The main factors affecting the use of herbal products were age, diagnosis of the disease, and treatment compliance problems. The most frequently used products were lemon, cinnamon, black cumin, ginger, turmeric, and dill. The participants main sources of information about HP/DS were friends/relatives, the internet/social media, and television, respectively. 74.8% of the participants using HP/DS did not inform their physcisian/pharmacist about such use, although 81.8% of these nevertheless wished to receive information from these occupational groups. CONCLUSION: Herbal product monitoring in patients should be performed in collaboration with pharmacists, herbal product use should be investigated, and counseling services should be made available in order to maintain and promote public health.

Apical extrusion of debris when using OneCurve, ProTaper Next and TruNatomy in curved canals.

BACKGROUND: The extrusion of apical debris is related to various factors, and may be affected by variations in technique or instrumentation system. Although the extrusion cannot be completely prevented, it is crucial to minimize the amount of extruded material. OBJECTIVES: The present study aimed to compare apical debris extrusion by the novel TruNatomy (TRN), OneCurve (OC) and ProTaper Next (PTN) instruments in curved root canals. MATERIAL AND METHODS: A total of 60 multi-rooted human mandibular molar teeth with moderate and severe curvature were selected and randomly divided into 3 groups. The root canals were prepared with the OC, TRN and PTN files. For collecting the debris extruded through the apical foramen, Eppendorf tubes were used. After the vaporizing period, the tubes were re-weighed, and the amount of the extruded debris was calculated by subtracting the initial weight from the final weight. Statistical analysis was performed with the Shapiro-Wilk and Kruskal-Wallis tests. The statistical significance level was set at p < 0.05. RESULTS: The least amount of debris was extruded with TRN and the greatest with PTN, but the difference between the groups was not significant (p = 0.257). CONCLUSIONS: All instrumentation systems were associated with debris extrusion. The tested file systems presented similar results in terms of apical debris extrusion in curved canals. The novel TRN system demonstrated promising results, comparable to OC and PTN.

Can signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1) be used as an indicator of endothelial dysfunction in acromegaly patients?

PURPOSE: Acromegaly is closely related to increased oxidative stress and endothelial dysfunction (ED). This study aimed to evaluate, for the first time in the literature, signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1) and endothelial nitric oxide synthase e(NOS) levels in the setting of acromegaly. METHOD: A total of 56 acromegaly patients and a control group composed of 30 healthy volunteers were included in this study. In the postoperative follow-up, patients were grouped as active or in-remission according to their GH and IGF-1 levels in oral glucose stimulation test (OGST). After detailed physical examination of acromegaly patients and the control subjects, 8-hour fasting blood samples were collected to evaluate biochemical parameters including lipid profile, anterior pituitary hormones, and SCUBE-1 and e(NOS) levels. RESULTS: Inactive and active acromegaly was noted in 78.6% and 21.4% of patients, respectively. The median (min-max) SCUBE-1 levels were significantly higher in the inactive acromegaly and active acromegaly groups than in the control group (1.6(0.4-2.4) and 1.8(1.1-2.5) vs. 0.4(0.2-1.0) ng/mL, respectively, p < 0.001 for each). The median (min-max) e(NOS) levels were significantly higher in the inactive acromegaly and active acromegaly groups than in the control group (132.7 (26.8-602.9) and 137.3 (69.7-488.7) vs. 83.9 (16.4-218.7) pg/mL, p = 0.018 and p = 0.048, respectively). We have also detected positive correlations of e(NOS) with leukocyte (r = 0.307, p = 0.021) and neutrophil counts (r = 0.309, p = 0.021). CONCLUSION: Our study revealed for the first time in literature that SCUBE-1 levels, being a novel marker for ED, were significantly higher in acromegaly patients than in control subjects. When supported with clinical studies, SCUBE-1can be used as an early indicator of endothelial damage in acromegaly patients.

Comparison of orlistat and orlistat plus metformin therapy between diabetic and nondiabetic groups.

OBJECTIVE: The objective of this study was to examine the effects of orlistat use on metabolic control and weight loss in diabetic and nondiabetic patients. METHODS: A total of 119 patients with body mass index≥40 kg/m2 and receiving orlistat therapy, who applied to the Endocrinology polyclinic between January 2016 and October 2019, were included. The patients' weight changes and biochemical values (i.e., fasting glucose, HbA1c, ALT, creatinine, and lipid parameters) were evaluated at the drug beginning and the last polyclinic control. The patients were divided into groups, whether they had diabetes or used metformin, and compared. RESULTS: The mean age of the 119 patients in the study was 45.3±11.5 years. A total of 94.1% of the patients were females and 5.9% were males. A total of 38.7% of the patients had diabetes and 29.4% had prediabetes. When the patients were compared to whether they had diabetes or used metformin, there was a statistically significant difference between the groups according to weight loss. The mean weight change of patients without diabetes and receiving metformin and orlistat was statistically significantly higher than that of patients with diabetes and receiving metformin and orlistat. DISCUSSION: It was determined that the weight loss effect of orlistat in obesity was seen in all groups, but this effect decreased in the diabetic group.

Efficacy of various activation techniques on tubule penetration of resin-based and bioceramic root canal sealers: An in vitro confocal microscopy study.

To compare the penetration of Ah Plus and MTA Fillapex after irrigation activation with sonic, passive ultrasonic, SWEEPS and XP-Endo Finisher using confocal microscopy. Instrumented root canals of 160 mandibular premolar teeth were allocated randomly to four groups (n = 40/group) and eight subgroups according to the activation techniques and canal sealers (n = 20/subgroup). After the obturation, three sections at 1-2, 5-6 and 9-10 mm levels from the apex were examined. Penetration area and maximum penetration depth values were represented as mean and standard deviation, and results below 0.05 were considered statistically significant. For penetration area and maximum penetration depth, the statistical difference was found in terms of material, device and region (Maximum penetration depth: p = 0.006, p < 0.001, p < 0.001; Penetration area: p = 0.004, p < 0.001, p < 0.001). SWEEPS was found to be relatively higher than other groups. Sealers presented similar results when evaluated independently of the region. The use of SWEEPS for irrigation activation is promising in terms of tubule penetration.

Impact of methylene-tetrahydrofolate reductase gene C677T and A1298C polymorphisms as a risk factor for hepatitis B virus infection.

Chronic hepatitis B infection caused by Hepatitis B virus (HBV), influences over two billion people worldwide despite having an effective vaccine. With a total prevalence of 4.57%, there are 3.3 million estimated HBV carriers in Türkiye. Methylene-tetrahydrofolate reductase (MTHFR) arrange folate metabolism through nucleic acid synthesis and DNA methylation. C677T (rs1801133, p.Ala222Val) and A1298C (rs1801131, p.Glu429Ala) polymorphisms of MTHFR gene have effect of reducing the activity of enzyme. We purposed to investigate the correlation between C677T and A1298C polymorphisms of MTHFR gene with HBV infection in a Turkish population. One hundred eighteen HBV-infected participants and ninety healthy controls were incorporated in this research. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was applied to discover the genotypes of MTHFR polymorphisms. We demonstrated that T allele and CT + TT genotype frequencies of C677T polymorphism were significantly increased in HBV-infected participants than healthy controls [p = 0.015, OR (95% Cl) = 1.7 (1.11-2.79) and p = 0.020, OR (95% Cl) = 1.9 (1.10-3.42), respectively). No significant associations were noted concerning the A1298C polymorphism (p > 0.05). CC-AA composite genotype was observed to be significantly elevated in healthy controls than HBV-infected participants (32.2% vs. 13.6%, p = 0.001). In addition, the frequency of T-C haplotype was found to be considerably higher in the patient group than control group (15.8% vs 11.8%, p = 0.018). In conclusion, we found that T allele of C677T polymorphism poses a risk factor for HBV infection. We also discovered a protective impact of the CC-AA composite genotype against HBV infection and a risk effect of the T-A haplotype for HBV-infection.

The effects of circulating MIR22-3p and MIR16-1-3p levels in different stages of subacute thyroiditis.

Subacute thyroiditis (SAT) is an inflammatory thyroid disease with a frequency is 5% among all thyroid diseases. miRNAs are endogenous, non-coding RNAs ranging in length from 19 to 25 nucleotides. They play an important role in the posttranscriptional regulation of gene expression. In this study, we aimed to investigate whether the expression levels of two circulating miRNAs, MIR22 and MIR16-1, can be used as a parameter in the diagnosis and follow-up of SAT disease. Fifty patients diagnosed with SAT and 41 healthy controls were included in this study. Expression levels of miRNAs were determined by real time-PCR method. Expression data of miRNAs were calculated by fold change (2-ΔΔCt) method. The statistical significance of miRNA expression was evaluated by t-test. The expression levels of MIR22-3p and MIR16-1-3p were not found to be statistically different between SAT patients and controls and also between the patients in different stages (hyperthyroid, euthyroid, and hypothyroid) of the disease. According to correlation analyses, we observed a positive strong correlation between erythrocyte sedimentation rate (ESR) and the expression levels of MIR22-3p and MIR16-1-3p (r = 0.960, p = 0.000 and r = 0.865, p = 0.006, respectively), and a positive strong correlation between fT4 and the expression levels of MIR22-3p in SAT patients in euthyroid stage (r = 0.712, p = 0.047). In this study, we showed that the expression levels of MIR22-3p and MIR16-1-3p have correlation with clinical characteristics of SAT disease. Our results suggest that MIR22 and MIR16-1 may be effective in the pathogenesis of SAT.

Comparison of orlistat and orlistat plus metformin therapy between diabetic and nondiabetic groups

SUMMARY OBJECTIVE: The objective of this study was to examine the effects of orlistat use on metabolic control and weight loss in diabetic and nondiabetic patients. METHODS: A total of 119 patients with body mass index≥40 kg/m2 and receiving orlistat therapy, who applied to the Endocrinology polyclinic between January 2016 and October 2019, were included. The patients' weight changes and biochemical values (i.e., fasting glucose, HbA1c, ALT, creatinine, and lipid parameters) were evaluated at the drug beginning and the last polyclinic control. The patients were divided into groups, whether they had diabetes or used metformin, and compared. RESULTS: The mean age of the 119 patients in the study was 45.3±11.5 years. A total of 94.1% of the patients were females and 5.9% were males. A total of 38.7% of the patients had diabetes and 29.4% had prediabetes. When the patients were compared to whether they had diabetes or used metformin, there was a statistically significant difference between the groups according to weight loss. The mean weight change of patients without diabetes and receiving metformin and orlistat was statistically significantly higher than that of patients with diabetes and receiving metformin and orlistat. DISCUSSION: It was determined that the weight loss effect of orlistat in obesity was seen in all groups, but this effect decreased in the diabetic group.

Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.

Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery.

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.

Copper induces cell death by targeting lipoylated TCA cycle proteins.

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

Dentinal tubule penetration of gutta-percha with syringe-mix resin sealer using different obturation techniques: A confocal laser scanning microscopy study.

This study aimed to evaluate dentinal tubule penetration of the root canal filling material using various techniques such as cold lateral compaction, new generation thermoplastic core carrier and continuous-wave obturation. The root canals of premolar teeth were instrumented, and the teeth were allocated randomly to three groups (n = 15/group). After the obturation with three different techniques, three sections of 2-mm thickness at 2, 5 and 8-mm from the apex were examined under a confocal laser scanning microscope. The data were analysed of variance with a significance level of P < 0.05. There was no significant difference between techniques when parameters were evaluated in total (penetration depth P = 0.418, penetration area P = 0.701). The mean value of the cold lateral compaction group for maximum penetration depth was obtained higher than continuous wave (P = 0.004), whilst there was no significant difference between the thermoplastic core carrier and the other groups.

A comparative investigation between ProTaper Next, Hyflex CM, 2Shape, and TF-Adaptive file systems concerning cyclic fatigue resistance.

Background. This study aimed to compare the cyclic fatigue resistance of ProTaper Next, Hyflex CM, 2Shape, and TF-Adaptive nickel-titanium endodontic file systems with various alloy properties and production methods and investigate the fractured cross-sectional surface of files due to cyclic fatigue by scanning electron microscopy (SEM). Methods. A total of 120 instruments were used (n=30). For standardization, #25/.06 apical diameter and taper angle were selected for each file system. The experiment of files was subjected to a static cyclic fatigue model. The time for files' failure was recorded with a digital chronometer and multiplied by the rotation speed to calculate the number of cycles. Kolmogorov-Smirnov, one-way ANOVA, and post hoc Bonferroni analysis were used for statistical analysis. Statistical significance was set at P < 0.05. Results. The number of cycles for the failure of files was compared between the groups, and significant differences were found (P < 0.05). The number of cycles for instrument failure was recorded from the highest to the lowest as follows: Hyflex CM, TF-Adaptive, ProTaper Next, and 2Shape. Conclusion. The files were fractured at different average numbers of cycles in an artificial canal in all the groups. The Hyflex CM demonstrated better cyclic fatigue resistance than TF Adaptive, ProTaper Next, and 2Shape file systems. Factors such as production patterns, alloy properties, and the phase in which the files were produced might affect the lifespan of file systems.

Effects of repeated sterilization cycles on the surface alterations of ProTaper Next, TF Adaptive, HyFlex CM, and 2Shape instruments.

Background. This study aimed to evaluate the effects of repeated sterilization cycles on the surface alterations of various nickel-titanium instruments, including ProTaper Next (PTN), TF Adaptive (TFA), HyFlex CM (HCM), and 2Shape (2S). Methods. Twenty-four new NiTi files of four different alloys were selected. The instruments in each group were divided into two equal groups, as follows: control and sterilization. The first group was chosen as the control without applying any sterilization procedure, while in group 2, five cycles of sterilization procedures were applied. The surface topographies were evaluated using scanning electron microscope (SEM) and atomic force microscope (AFM). The root mean square (RMS) and maximum height (MH) values and three-dimensional images were recorded. The data were analyzed with the Shapiro-Wilk test, one-way ANOVA, and post hoc Tukey tests. The statistical significance level was set at P ≤ 0.05. Results. Before the experiment, HCM demonstrated the highest RMS value, and 2S showed the lowest. After the procedures, the RMS and MH values deteriorated on the surface of PTX, TFA, and 2S (P < 0.001). The HCM was not affected by sterilization processes (P > 0.05). Conclusion. The initial irregularity on the surface did not affect the rate of alteration. The HCM files demonstrated superior surface properties after several cycles of sterilization. The PTN, TFA, and 2S presented similar surface responses after five cycles of autoclave sterilization.

Clinical research of insulin glargine U300 in type 1 diabetes mellitus patients with frequent hypoglycaemia: real-world experience.

INTRODUCTION: We aimed to see whether insulin glargine U300 can provide better blood glucose control while reducing hypoglycaemia in a more homogeneous population compared to previous studies. MATERIAL AND METHODS: The retrospective study included type 1 diabetes mellitus (T1DM) patients with frequent hypoglycaemia. For evaluation of fasting blood glucose, haemoglobin glycated (HbA1c) and weight at 6 months and 12 months (final), observation windows of 120-240 days (4-8 months) and 240-480 days (9-16 months) after insulin glargine U300 initiation, respectively, were permitted. Mean follow-up time was 12 months. Hypoglycaemia was defined as blood glucose level < 70 mg/dl, either symptomatic or asymptomatic, measured in hospital or at home. RESULTS: Forty-four patients were included in the study, and 35 patients completed the study - 20 (57.1%) females and 15 (42.9%) males, with a mean age of 24.1 ±6.6 years. Mean body mass index was 24.4 ±7.4 kg/m2. A significant decrease was not found between baseline and HbA1c values at 6 months (p = 0.199), but a significant decrease was found in the final period (between 9-16 months) (p = 0.025). Hypoglycaemic events occurred in all patients (100%) before using insulin glargine U300, while the incidence of hypoglycaemic events gradually decreased to 74.3%, 68.6%, and 68.6% between months 1-3, 3-6, and 6-9, respectively. Of the 26 patients who declared their level of satisfaction, 23 (88.5%) were satisfied, 2 (7.7%) indicated that there was no significant difference, and 1 (3.8%) patient was unsatisfied. CONCLUSIONS: Over 9-16 months of follow-up, insulin glargine U300 led to a significant reduction not only of HbA1c levels but also of the frequency of hypoglycaemia, and also yielded high satisfaction rates.

Clinical research of insulin glargine U300 basal-bolus therapy and insulin degludec/aspart co-formulation in type 2 diabetes mellitus: A real world experience.

AIMS: Insulin degludec/aspart (IDegAsp) and insulin glargine U300 (IGlarU300) have recently emerged as popular new-generation insulin analogues. The aim of this real-life study was to investigate the patient profiles in which IGlarU300 and IDegAsp were preferred and the insulin combinations after which each of them were mostly used and also to analyse the effect of these two insulin analogues on blood glucose regulation and hypoglycaemia. MATERIALS AND METHODS: The retrospective study included 174 patients that were switched from basal insulin, basal-bolus insulin, or premixed insulin to IGlarU300 or IDegAsp due to uncontrolled blood glucose levels or history of hypoglycaemia. Hypoglycaemia, body weight, body mass index (BMI), fasting plasma glucose (FPG) and HbA1c levels over 3-month periods were evaluated for each patient. RESULTS: There were 84 and 90 patients in the IGlarU300 and IDegAsp groups, respectively. Body weight was similar in both groups. Baseline FPG and HbA1c levels in the IGlarU300 and IDegAsp groups were 9.0%, 175.5 mg/dL and 9.4%, 193.5 mg/dL, respectively. A significant decrease was found in FPG and HbA1c levels in both groups (138.5, 7.8 vs 141.5, 8.2; P < .001 for all). Moreover, a significant weight gain was observed in both groups (P < .05 for both). The prevalence of hypoglycaemia in both groups decreased significantly and consistently between months 1 and 9 (P < .001). At month 12, although this decrease continued in the IGlarU300 group (P = .013), no significant decrease was observed in the IDegAsp group (P = .057). CONCLUSION: Both twice-daily IDegAsp ± bolus insulin and IGlarU300 basal bolus insulin therapies are effective and safe treatment modalities.

SafePredict: A Meta-Algorithm for Machine Learning That Uses Refusals to Guarantee Correctness.

SafePredict is a novel meta-algorithm that works with any base prediction algorithm for online data to guarantee an arbitrarily chosen correctness rate, 1-ϵ, by allowing refusals. Allowing refusals means that the meta-algorithm may refuse to emit a prediction produced by the base algorithm so that the error rate on non-refused predictions does not exceed ϵ. The SafePredict error bound does not rely on any assumptions on the data distribution or the base predictor. When the base predictor happens not to exceed the target error rate ϵ, SafePredict refuses only a finite number of times. When the error rate of the base predictor changes through time SafePredict makes use of a weight-shifting heuristic that adapts to these changes without knowing when the changes occur yet still maintains the correctness guarantee. Empirical results show that (i) SafePredict compares favorably with state-of-the-art confidence-based refusal mechanisms which fail to offer robust error guarantees; and (ii) combining SafePredict with such refusal mechanisms can in many cases further reduce the number of refusals. Our software is included in the supplementary material, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TPAMI.2019.2932415.