Adaptive response of resistant cancer cells to chemotherapy

Despite advances in cancer therapeutics and the integration of personalized medicine, the development of chemoresistance in many patients remains a significant contributing factor to cancer mortality. Upon treatment with chemotherapeutics, the disruption of homeostasis in cancer cells triggers the adaptive response which has emerged as a key resistance mechanism. In this review, we summarize the mechanistic studies investigating the three major components of the adaptive response, autophagy, endoplasmic reticulum (ER) stress signaling, and senescence, in response to cancer chemotherapy. We will discuss the development of potential cancer therapeutic strategies in the context of these adaptive resistance mechanisms, with the goal of stimulating research that may facilitate the development of effective cancer therapy.     

A systematic review of the methodological quality of economic evaluations in genetic screening and testing for monogenic disorders

PurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examined opportunities for improvement.MethodsWe searched PubMed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the British Medical Journal checklist.ResultsAcross the 47 identified studies, there were substantial variations in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulations that compared between 2 and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.ConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection; (2) use of uncertainty/sensitivity analyses; and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.     

Factors associated with clinically significant hypoglycemia in patients with type 1 diabetes using sensor-augmented pump therapy with predictive low-glucose management: A multicentric study on iberoamerica

Background and aimsDespite using sensor-augmented pump therapy (SAPT) with predictive low-glucose management (PLGM), hypoglycemia is still an issue in patients with type 1 Diabetes (T1D). Our aim was to determine factors associated with clinically significant hypoglycemia (<54 mg/dl) in persons with T1D treated with PLGM-SAPT.Methodology: This is a multicentric prospective real-life study performed in Colombia, Chile and Spain. Patients with T1D treated with PLGM-SAPT, using sensor ≥70% of time, were included. Data regarding pump and sensor use patterns and carbohydrate intake from 28 consecutive days were collected. A bivariate and multivariate Poisson regression analysis was carried out, to evaluate the association between the number of events of <54 mg/dl with the clinical variables and patterns of sensor and pump use.Results188 subjects were included (41 ± 13.8 years-old, 23 ± 12 years disease duration, A1c 7.2% ± 0.9). The median of events <54 mg/dl was four events/patient/month (IQR 1–10), 77% of these events occurred during day time. Multivariate analysis showed that the number of events of hypoglycemia were higher in patients with previous severe hypoglycemia (IRR1.38; 95% CI 1.19–1.61; p < 0.001), high glycemic variability defined as Coefficient of Variation (CV%) > 36% (IRR 2.09; 95%CI 1.79–2.45; p < 0.001) and hypoglycemia unawareness. A protector effect was identified for adequate sensor calibration (IRR 0.77; 95%CI 0.66–0.90; p:0.001), and the use of bolus wizard >60% (IRR 0.74; 95%CI 0.58–0.95; p:0.017).ConclusionIn spite of using advanced SAPT, clinically significant hypoglycemia is still a non-negligible risk. Only the identification and intervention of modifiable factors could help to prevent and reduce hypoglycemia in clinical practice.     

Mildly decreased preoperative bilirubin levels are associated with infections after shoulder and knee arthroplasty

Increasing numbers of arthroplasties are also accompanied by postoperative infections. The main purpose was to evaluate preoperative serum bilirubin levels between patients with and without infections after shoulder and knee arthroplasties. For this retrospective case-control single-center study, a total of 108 patients were extracted from a prospectively collected database. Eighteen patients with infections after shoulder (n = 8) and knee (n = 10) arthroplasty were matched by age, gender, and implant type in a 1:5-scenario to 90 patients (40 shoulders and 50 knees) without postoperative infection. Demographic data, preoperative blood parameters, and postoperative infection-related outcomes were evaluated. Total bilirubin was the only preoperative parameter significantly different between the infection (8.21 ± 3.25 μmol/L or 0.48 ± 0.19 mg/dL) and noninfection (10.78 ± 4.62 μmol/L or 0.63 ± 0.27 mg/dL; P = .014) group, while C-reactive protein and other liver parameters were similar between the groups. Significantly more controls (92.1%) had preoperative bilirubin levels above 8.72 μmol/L or 0.51 mg/dL than cases (7.9%; P = .007). The 5-year infection survival-rate was 65.6% for patients with preoperative bilirubin levels < 8.72 μmol/L or < 0.51 mg/dL and 91.2% with ≥ 8.72 μmol/L or ≥ 0.51 mg/dL. Mildly decreased preoperative bilirubin levels with a cutoff at 8.72 μmol/L or 0.51 mg/dL were significantly associated to patients with infections after shoulder and knee arthroplasty. There were no differences in other blood parameters or comorbidities between patients with infections and their matched-controls.     

Natural compulsive‐like behaviour in the deer mouse (Peromyscus maniculatus bairdii) is associated with altered gut microbiota composition

Obsessive–compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut–brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive–compulsive‐like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific‐pathogen‐free bred and housed large (LNB) and normal (NNB) nest‐building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest‐building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut‐off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof‐of‐concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive–compulsive‐like behaviours.     

Accuracy of direct examination and culture as compared to the anatomopathological examination for the diagnosis of chromoblastomycosis: a systematic review

BackgroundChromoblastomycosis is a skin infection caused by dematiaceous fungi that take the form of muriform cells in the tissue. It mainly manifests as verrucous plaques on the lower limbs of rural workers in tropical countries.ObjectivesThe primary objective of this review is to evaluate the accuracy of diagnostic methods for the identification of chromoblastomycosis, considering the histopathological examination as the reference test.MethodsMEDLINE, LILACS and Scielo databases were consulted using the terms “chromoblastomycosis” AND “diagnosis”. The eligibility criteria were: studies that evaluated the accuracy of tests for the diagnosis of chromoblastomycosis. Eleven studies were selected. Statistical analysis included the calculation of sensitivity and specificity of the diagnostic methods.ResultsConsidering the histopathological examination as the reference test, the culture showed a sensitivity (S) of 37.5% - 90.9% and a specificity (Sp) of 100%; while direct mycological examination showed S = 50% - 91.6% and Sp of 100% . Considering the culture as the reference test, the serology (precipitation techniques) showed S of 36% - 99%; and Sp of 80% - 100%; while the intradermal test showed S of 83.3% - 100% and Sp of 99.4% - 100%.Study limitationsThe small number of studies and very discrepant sensitivity results among them do not allow the calculation of summary measures through a meta-analysis.ConclusionsDirect mycological examination, culture, intradermal test and serology show sensitivity and specificity values ??for the diagnosis of chromoblastomycosis with no significant difference between the studies.