Miracle-dz/UniFAR-FTUs huggingface dataset:
Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg (‘high-dose’) imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.
Tacrolimus dose requirement based on the CYP3A5 genotype in renal transplant patients

Tacrolimus (FK506) and cyclosporine A (CsA) are widely used to protect graft function after renal transplantation. The aim of the present study is to determine whether the single nucleotide polymorphism of CYP3A5 is a predictive index of FK506 dose requirement, and also the selection yardstick of FK506 or CsA treatment.We tested archival peripheral blood of 218 kidney recipients for CYP3A5 genotyping with PCR-SSP. Meanwhile, the dose of FK506 and CsA was recorded, blood concentration of the drugs was measured, and graft outcome was monitored.These results indicate that CYP3A5*AA/AG carriers need higher FK506 dose than CYP3A5*GG homozygote to achieve the target blood concentration. For CYP3A5*GG carriers, taking FK506 or CsA are both advisable. CYP3A5*AA/AG carriers preferred to CsA treatment depending on the graft outcomes and drug costs. CYP3A5 genotyping is a new approach to detecting FK506 dose requirement and a predictive index for the FK506 or CsA treatment selection in kidney recipients.
Resilience, sleep quality and morningness as mediators of vulnerability to depression in medical students with sleep pattern alterations

ABSTRACT The medical career is considered highly stressful, especially during internships when academic and clinical demands, combined with changes in sleep patterns, increase students’ likelihood to develop depression. Resilience, which is considered as opposite vulnerability to stress and, along with another protective factor, namely morningness, may cause a student to be less reactive to stimuli and, therefore, less prone to depression. The objective of this study was to evaluate the role of resilience and morningness facing to sleep quality and main risk factors, on the development of depression symptoms in a group of students with sleep pattern alterations. To this end, an observational and longitudinal study was performed with 30 undergraduate interns, with an average age of 22.63 years (SE ± 0.13), 33% men and 67% women. A survey was conducted in three different times during the year of internship: at the beginning (T1), in the middle (T2) and the end (T3). The instruments were the Brief Resilience Scale, Composite Scale of Morningness, Pittsburgh Sleep Quality Index and Patient Health Questionnaire. The path analysis examined the roles of morningness, sleep quality and resilience as potential mediators between family history of depression and depression symptoms at different times. The results showed that resilience had a protective effect on depression symptoms at T2 (β = −0.18, p < 0.05) and with greater power at T3 (β = −0.41, p < 0.05), as did morningness, although less strongly, on the symptoms at T3 (β = −0.13, p < 0.05). A relationship between these two mediating variables was also observed (β = 0.30, p < 0.05). The initial sleep quality had an effect on the increase of depression symptoms at T1 (β = 0.61, p < 0.05) and T3 (β = 0.21, p < 0.05), while family history of depression had a direct effect on the measures of depression at T2 (β = 0.49, p < 0.05) and T3 (β = 0.19, p < 0.05). Aside from personal risk factors, it is possible to conclude that the levels of resilience, morningness and sleep quality manifested by students at the beginning of their internship may explain the decrease in depression symptoms at the end of the course.
Uniportal video-assisted thoracoscopic early learning curve for major lung resections in a high volume training center.

Background Uniportal video-assisted thoracoscopic surgery (VATS) for major lung resections is a novel upcoming approach, with increasing popularity worldwide. However, there is little literature regarding this technique's learning curve. We present our experience of the early learning curve of the uniportal VATS major lung resections in a high volume training centre, whilst analysing the advantages. Methods Sixty selected consecutive patients underwent uniportal VATS major lung resections, for early stage disease of NSCLC and benign disease during the learning curve of a single surgeon in a high volume training centre from July to October 2015. The perioperative variables and outcomes were collected prospectively and analysed retrospectively. Results The 60 patients undergoing a uniportal VATS approach included 47 lobectomies and 13 segmental resections, among which 56 cases of lung cancer and 4 of benign pulmonary disease were noted. Right upper lobectomy (RUL) was the most common procedure (42%). The mean operation time was 192.3±45.4 minutes, average blood loss was 167.9±94.4 mL. For patients with lung cancer, the total amount of lymph node stations sampled or dissected were 4.2±0.8. Chest drain duration was 2.9±0.9 days and length of hospital stay (LOS) was 4.38±1 days. Prolonged air leak (PAL) was the most common complication in 8.3% of the cases. PAL was the cause of prolonged hospital stay. One case was converted to thoracotomy for major bleeding. There were no deaths 30 days after surgery or readmissions. All cases had a R0 complete cancer resection on histology. Conclusions The uniportal VATS lobectomy and segmentectomy early learning curve in a high volume training centre is a safe venture, allowing surgeons to reach an expert level faster and perform more complex resections with a shorter training time.
Innate Immunity Cells and the Neurovascular Unit

Recent studies have clarified many still unknown aspects related to innate immunity and the blood-brain barrier relationship. They have also confirmed the close links between effector immune system cells, such as granulocytes, macrophages, microglia, natural killer cells and mast cells, and barrier functionality. The latter, in turn, is able to influence not only the entry of the cells of the immune system into the nervous tissue, but also their own activation. Interestingly, these two components and their interactions play a role of great importance not only in infectious diseases, but in almost all the pathologies of the central nervous system. In this paper, we review the main aspects in the field of vascular diseases (cerebral ischemia), of primitive and secondary neoplasms of Central Nervous System CNS, of CNS infectious diseases, of most common neurodegenerative diseases, in epilepsy and in demyelinating diseases (multiple sclerosis). Neuroinflammation phenomena are constantly present in all diseases; in every different pathological state, a variety of innate immunity cells responds to specific stimuli, differentiating their action, which can influence the blood-brain barrier permeability. This, in turn, undergoes anatomical and functional modifications, allowing the stabilization or the progression of the pathological processes.
Clinical management in the takotsubo syndrome

ABSTRACT Introduction: Takotsubo syndrome (TS) is an increasingly recognized acute heart failure syndrome which is self-limiting in most cases but can result in life-threatening complications. TS is difficult to distinguish from acute myocardial infarction (AMI) early in the disease course and currently lacks evidence-based treatment recommendations. Areas covered: Based on the available literature this systematic review discusses the clinical management of patients with TS during (i) the diagnostic workup; (ii) acutely after establishing the TS diagnosis; and (iii) after recovery of cardiac function. Expert commentary: Since TS is self-limiting in most cases it is recommended to refrain from unnecessary treatment (the do no harm principle) when managing patients with TS. The management of patients with TS should focus on careful monitoring of ECG and hemodynamics, and on preventing and treating complications. Because catecholamine-mediated inotropic overstimulation is implicated in the pathogenesis of TS, and because inotropic drugs have been associated with worse outcomes for patients with TS, we recommend the treating physician to avoid these drugs. Instead, mechanical assist devices should be considered early for patients with TS who develop cardiogenic shock with signs of end-organ hypo-perfusion.
Chlorpyrifos- and Dichlorvos-Induced Oxidative and Neurogenic Damage Elicits Neuro-Cognitive Deficits and Increases Anxiety-Like Behavior in Wild-Type Rats

The execution of agricultural activities on an industrial scale has led to indiscriminate deposition of toxic xenobiotics, including organophosphates, in the biome. This has led to intoxication characterized by deleterious oxidative and neuronal changes. This study investigated the consequences of oxidative and neurogenic disruptions that follow exposure to a combination of two organophosphates, chlorpyrifos (CPF) and dichlorvos (DDVP), on neuro-cognitive performance and anxiety-like behaviors in rats. Thirty-two adult male Wistar rats (150–170 g) were randomly divided into four groups, orally exposed to normal saline (NS), DDVP (8.8 mg/kg), CPF (14.9 mg/kg), and DDVP + CPF for 14 consecutive days. On day 10 of exposure, anxiety-like behavior and amygdala-dependent fear learning were assessed using open field and elevated plus maze paradigms, respectively, while spatial working memory was assessed on day 14 in the Morris water maze paradigm, following three training trials on days 11, 12, and 13. On day 15, the rats were euthanized, and their brains excised, with the hippocampus and amygdala removed. Five of these samples were homogenized and centrifuged to analyze nitric oxide (NO) metabolites, total reactive oxygen species (ROS), and acetylcholinesterase (AChE) activity, and the other three were processed for histology (cresyl violet stain) and proliferative markers (Ki67 immunohistochemistry). Marked (p ≤0.05) loss in body weight, AChE depletion, and overproduction of both NO and ROS were observed after repeated exposure to individual and combined doses of CPF and DDVP. Insults from DDVP exposure appeared more severe owing to the observed greater losses in the body weights of exposed rats. There was also a significant (p ≤0.05) effect on the cognitive behaviors recorded from the exposed rats, and these deficits were related to the oxidative damage and neurogenic cell loss in the hippocampus and the amygdala of the exposed rats. Taken together, these results provided an insight that oxidative and neurogenic damage are central to the severity of neuro-cognitive dysfunction and increased anxiety-like behaviors that follow organophosphate poisoning.
Prevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance

Purpose The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma. Method A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined. Results A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes. Conclusion The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.
Interactions of protons with single open L-type calcium channels. pH dependence of proton-induced current fluctuations with Cs+, K+, and Na+ as permeant ions

We studied the pH dependence of the proton-induced current fluctuations that appear in single open L-type Ca channels when monovalent ions are the charge carriers. We used different methods of analysis to obtain kinetic measurements even under conditions where the individual transitions were too fast to be resolved directly as discrete current steps between two conductance levels. The reciprocal of the dwell times at the high conductance level increased linearly with the pipette proton activity, with a slope that was similar for Cs, K, and Na as permeant ions. Contrary to the expectation for a simple model in which the high and low conductances represent the unprotonated and protonated states of the channel, respectively, the dwell times at the low conductance level were also pH dependent and lengthened with increasing proton activity. At all pH values the dwell times at the low conductance level were longest with Cs as permeant ion and shortened in the order Cs greater than K greater than Na. We introduce a more general model of the protonation cycle in which the channel is represented by four states and can be protonated and deprotonated both at the high and low conductance levels. The conductance change is represented by a conformational change of the channel protein. We discuss the validity of this model and its implications for the mechanism by which protons interact with ion permeation through L-type Ca channels.
Spatial Distribution of Forensically Significant Blow Flies in Subfamily Luciliinae (Diptera: Calliphoridae), Chiang Mai Province, Northern Thailand: Observations and Modeling Using GIS

Blow flies of the subfamily Luciliinae (Diptera: Calliphoridae) are one of the main forensically important subfamilies globally. In addition to being used to estimate the minimum post-mortem interval (PMImin), assuming colonization occurred after death, blow fly specimens found infesting a human corpse are used to determine if the corpse was relocated or if the individual ingested narcotics prior to death. The presence of these blow flies in a given area is strongly influenced by abiotic and biotic factors, such as temperature, elevation, and habitat. Having this information, along with geographical distributions and the characteristics of preferred habitats, is necessary to better understand the biology of this group. This study aimed to characterize the spatial distribution of Luciliinae throughout 18 sampling sites within six ecozones (disturbed mixed deciduous forest, mixed deciduous forest, mixed orchard, paddy field, lowland village, and city/town) in central Chiang Mai Province, northern Thailand over one year (May 2009–May 2010). The purpose of the study was to elucidate the relationship of blow fly species composition with environmental abiotic factors (e.g., temperature, relative humidity, light intensity), and to predict the distribution of the common species within this subfamily using GIS. Adult collections were performed biweekly, baited with one-day-old beef offal. A total of 2331 Luciliinae flies trapped, comprising eight species, of which the four predominant species were Hemipyrellia ligurriens (Wiedemann) (n = 1428; 61.3%), Lucilia porphyrina (Walker) (n = 381; 16.3%), Hemipyrellia pulchra (Wiedemann) (n = 293; 12.6%), and Lucilia papuensis Macquart (n = 129; 5.5%). Population density across species varied seasonally, peaking in August 2009 coinciding with the rainy season. Predicting population composition was based on a model developed with ArcGIS 9.2, which utilized environmental variables (temperature, relative humidity, and light intensity) in conjunction with abundance data. Models indicated H. ligurriens had the most widespread geographic distribution, while H. pulchra was predicted to occur largely in mixed orchards and lowland villages. Lucilia porphyrina and L. papuensis were less widespread, restricted mainly to mixed deciduous forest. This model, along with knowledge of forensic information, may be useful under certain investigations where the corpse may have been relocated.
Association of P73 polymorphisms with susceptibilities of cervical carcinoma: a meta-analysis

Objective The relation between P73 gene polymorphism and cervical cancer has not been determined. At present, we utilized a meta-analysis method to elucidate the association between P73 and cervical cancer. Results The present study included 635 patients with cervical cancer and 998 cancer-free control subjects. Using meta-analysis, we found a significant association of P73 genetic polymorphism with cervical cancer in a recessive model [OR = 0.91, 95% CI: 0.84−0.98; P = 0.02. ]. However, this association was not find in a dominant model [OR = 0.76, 95% CI (0.45−1.27); P = 0.29], in a co-dominant model [OR = 1.01; 95% CI: 0.98–1.04, P = 0.56] or in an allelic model [OR = 0.97, 95% CI: 0.93−1.00; P = 0.09]. Materials and Methods To further evaluate the relation between the P73 gene polymorphism and cervical cancer, we selected 5 case-control studies related to P73 gene polymorphism and cervical cancer by searching CNKI, VIP, WanFang, PubMed and EMbase database. We utilized Q-test and I2 test to test the heterogeneity between each study. The fixed effects model was utilized to calculate the odds ratio (OR) and its 95% confidence interval. Conclusions Our results suggest that P73 gene polymorphism was associated with the risk of cervical cancer. However, our conclusion still requires large sample size of case-control studies or cohort studies to further confirm this result.
Evaluation of clinical meaningfulness of estrogen plus progesterone oral capsule (TX-001HR) on moderate to severe vasomotor symptoms

Objective: The aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus. Methods: In the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (≥7/d or ≥50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17&bgr;-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods. Results: In the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression–based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥25 moderate to severe VMS: 82-88% vs 69%; all, P < 0.05) and CID (weekly reduction of ≥39 VMS: 68%-73% vs 52%; all, P < 0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life–based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥34 VMS: 74%-81% vs 55%; all, P < 0.01) and CID (weekly reduction of ≥44 VMS: 61%-69% vs 42%; all, P < 0.01) at week 12. Conclusions: TX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.
A multi-level analysis of individual- and school-level correlates of physical fitness in children

Abstract Background: Children’s physical fitness is potentially influenced by biological, behavioural and environmental factors. Aim: To investigate the importance of individual-level and school-level characteristics in explaining variation in children’s physical fitness. Subjects and methods: The sample comprised 354 Portuguese children, aged 5–10 years. Physical fitness [(handgrip (HG) strength, standing long jump (SLJ), shuttle-run (SR), total physical fitness score (PFz)], gross motor coordination (GMC) and body mass index (BMI) were assessed. Moderate-to-vigorous physical activity (MVPA) was objectively monitored; birth weight and socio-economic status (SES) were obtained by questionnaire. School contexts were assessed via an objective audit. Multilevel models using the Bayesian approach were used. Results: Age was positively associated with HG, SLJ and PFz (p < 0.05); BMI was positively associated with HG (p < 0.05) and GMC with all physical fitness components (p < 0.05); MVPA was only associated with PFz (p < 0.05); children with level A SES outperformed those with level C SES in HG (p < 0.05), but those with level B SES outperformed their level A SES peers in SR (p < 0.05). Within the school context, no equipment for physical education was negatively associated with HG (p < 0.05). Conclusion: In the primary school years, individual-level characteristics were more important than the school context in explaining variations in physical fitness.