Miracle-dz/UniFAR-FTUs huggingface dataset:
Is the revised International staging system for myeloma valid in a real world population?

Larson, R.A. & Bloomfield, C.D. (2005) Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B Study. Journal of Clinical Oncology, 23, 5705–5717. Qin, Y.Z. , Xu, L.P., Chen, H. , Jiang, Q. , Wang, Y. , Jiang, H. , Zhang, X.H. , Han, W. , Chen, Y.H. , Wang, F.R. , Wang, J.Z. , Zhu, H.H. , Liu, Y.R. , Jiang, B. , Liu, K.Y. & Huang, X.J. (2015) Allogeneic stem cell transplant may improve the outcome of adult patients with inv(16) acute myeloid leukemia in first complete remission with poor molecular responses to chemotherapy. Leukemia & Lymphoma, 56, 3116–3123. Schlenk, R.F. , Benner, A. , Krauter, J., B€ uchner, T. , Sauerland, C. , Ehninger, G. , Schaich, M. , Mohr, B. , Niederwieser, D. , Krahl, R. , Pasold, R. , D€ ohner, K. , Ganser, A. , D€ ohner, H. & Heil, G. (2004) Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. Journal of Clinical Oncology, 22, 3741– 3750. Wang, Y. , Liu, Q.F. , Xu, L.P., Liu, K.Y. , Zhang, X.H. , Ma, X. , Fan, Z.P., Wu, D.P. & Huang, X.J. (2015) Haploidentical vs. identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood, 125, 3956–3962. Yoon, J.H. , Kim, H.J., Kim, J.W. , Jeon, Y.W. , Shin, S.H. , Lee, S.E. , Cho, B.S., Eom, K.S. , Kim, Y.J., Lee, S. , Min, C.K. , Cho, S.G. , Lee, J.W. , Min, W.S. & Park, C.W. (2014) Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation. Bone Marrow Transplantation, 49, 1466–1474.
Clinical utility of next‐generation sequencing‐based minimal residual disease in paediatric B‐cell acute lymphoblastic leukaemia

We assessed the clinical utility of next‐generation sequencing (NGS)‐based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B‐cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre‐ (4–5 months) and post‐ (24 months) maintenance therapy time points, and at relapse. We identified leukaemia‐specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia‐free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS‐MRD for patients with B‐cell ALL.
Biomimetic Syntheses of (−)-gochnatiolides A−c and (−)-ainsliadimer B

We report the first biomimetic syntheses of (−)-gochnatiolides A−C and (−)-ainsliadimer B based on our proposed biogenetic pathway. Our synthesis features one-pot cascade transformations including Saegusa oxidation, intermolecular Diels−Alder cycloaddition, and radical-mediated allylic oxidation, which allow for the rapid generation of (−)-gochnatiolides A−C in a collective manner. We also disclose an unprecedented " copper effect " on the stereochemical outcome of the radical-mediated allylic oxidation. Our synthetic endeavors led to the structural reassignment of (−)-gochnatiolide B. Ultimately, a biomimetic transformation from gochnatio-lide B to ainsliadimer B was achieved through a remarkable direct enone hydration. T he guaianolide-type sesquiterpenoid dimers represent a unique class of sesquiterpenoid natural products that exhibit a wide array of biological activities, including antitumor, anti-inflammation, and anti-HIV activities. 1 Biosynthetically, most of these molecules originate from two monomeric units via either Diels−Alder or hetero-Diels−Alder cycloadditions. Although a number of remarkable syntheses of disesquiterpe-noids have been reported, 2 significant challenges still exist in exploring the biomimetic routes. Gochnatiolides A (1), B (2), and C (3) (Figure 1) were initially isolated by Robinson and co-workers from Gochnatia species in 1980s. 3 More recently, Zhang and co-workers also isolated 1 and 3 4 as well as a related natural product, ainsliadimer B (4), from Ainsliaea fulvioides, together with two unprecedented sesquiterpene trimers, ansliatrimers A (5) and B (6). 5 Gochnatiolides A−C and ainsliadimer B all possess a complex heptacyclic ring system with an intriguing spiro[4,5]decane moiety. As part of an ongoing program aimed at the development of a general and biomimetic approach toward this unique family of sesquiterpe-noids, we now report the first syntheses of 1−4, which are guided by our proposed biosynthetic pathway. The synthetic studies also enabled us possibly to revise the originally proposed structure of gochnatiolide B (2′). We envisioned that biosynthetically the monomeric sesquiterpene lactone dehydrozaluzanin C (7), which was readily prepared in 11 steps from α-santonin, could serve as a common precursor for both gochnatiolides and ainsliadimers through three pathways (Scheme 1). 2c In a previous study, we demonstrated that the BINOL-promoted hetero-Diels−Alder dimerization of 7 smoothly realizes a biomimetic approach to afford the key homodimer 8, which was further elaborated to generate (+)-ainsliadimer A (9) in two steps (Scheme 1, pathway A). 2c Concurrent with these efforts, we also became interested in exploring the feasibility of constructing the gochnatiolide skeleton from 7 through Diels−Alder cyclo-addition. We hypothesized two biosynthetically inspired pathways for gochnatiolides: In …
Early response does not predict outcome in children and adolescents with chronic myeloid leukaemia treated with high‐dose imatinib

The achievement of early response has been shown to predict a significantly better outcome in adults with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with either imatinib (IM) or second-generation tyrosine kinase inhibitors (TKIs) (Branford et al, 2012; Hanfstein et al, 2012; Marin et al, 2012; Jain et al, 2013; Jabbour et al, 2014). Recently, early molecular response (EMR) was also reported to predict a better outcome in 40 CP-CML children treated with IM at a standard dose (260 mg/m/day) (Millot et al, 2014). We hereby analysed the predictive value of the BCR-ABL1 transcript levels at 3 months in terms of responses and outcome in a cohort of children and adolescents with CP-CML treated with high-dose IM at 11 Italian centres. This study (CMLPetit-01) was approved by the Institutional Ethics Committees. From March 2001 to March 2014, 53 patients younger than 18 years of age with a newly diagnosed CML in CP were treated with IM at a dose of 340 mg/m/day. Cytogenetics and quantitative reverse transcription polymerase chain reaction (qPCR) analysis were planned on bone marrow (BM) every 3 months and qPCR on peripheral blood (PB) monthly, as previously described (Giona et al, 2015). Haematological and cytogenetic response (CyR) criteria were defined according to the European LeukaemiaNet recommendations (Baccarani et al, 2009). Major molecular response (MMR) was defined as ≤0 1% BCR-ABL1 according to the International Scale (IS), while molecular response (MR) was considered as ≤0 01% BCR-ABL1 IS. Complete molecular response (CMR) was used to indicate levels of disease ≤0 0032% BCR-ABL1 IS or undetectable. Transcript levels ≤10% and ≤1% BCR-ABL1 IS at 3 months after starting IM were defined as EMR and deep EMR, respectively. Forty-four CP-CML patients (27 males, 17 females; median age: 11 years, range 3 to 15) who had available BCR-ABL1 levels at 3 months and had been followed for at least 12 months were included in this analysis. Overall, 92 5%, 85%, 56% and 39% of patients achieved a complete CyR (CCyR), MMR, MR and CMR after a median time of 6 2 (range 3 5–8 6), 13 4 (range 9 4–19 7), 14 9 (range 10 1– 24 1) and 15 (range 10 1–24 8) months, respectively. Three months after the start of IM, BCR-ABL1 transcript levels >10% IS were detected in 9/44 (20 5%) patients, whereas 18/ 44 (41%) and 17/44 (38 5%) patients had BCR-ABL1 IS of
Detection of ALECT2 amyloidosis by positron emission tomography–computed tomography imaging with florbetapir

A 69-year-old Mexican female with end stage renal disease on haemodialysis secondary to biopsy-confirmed leucocyte cell-derived chemotaxin 2 (ALECT2) amyloidosis underwent a positron emission tomography (PET) computed tomography (CT) scan with florbetapir F, a US Food and Drug Administration-approved radiotracer for detection of b-amyloid in the brain. Green arrows highlight diffuse intense activity above normal background in the lungs (maximum standardized uptake value [SUVmax] 10 0), spleen (SUVmax 40 6), adrenal glands (SUVmax 12 3), kidneys (SUVmax 16 3) and bone marrow (images). These organs normally have low activity on florbetapir PET/CT. The activity pattern is consistent with pathological data on the distribution of amyloidosis in this disease. Unlike transthyretin-related (ATTR) and light chain-related (AL) amyloidosis, there is normal background activity in the heart of this patient, which is consistent with autopsy data showing cardiac sparing in ALECT2 amyloidosis. The most remarkable finding in this patient is the uptake in the kidney because she makes little urine and is on chronic haemodialysis. ALECT2 amyloidosis is now recognized as the third most common type of renal amyloidosis in the United States, predominately in patients of Mexican or Native American descent. Cases have also been described in patients of Egyptian, Indian and Arab descent. The lack of cardiac or nerve involvement makes ALECT2 amyloidosis difficult to recognize and no laboratory test currently exists for screening. The use of florbetapir PET/CT could serve as a screening test for this at-risk population.
Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations

Systematic screening identified patients with an iron refractory iron deficiency anaemia (IRIDA) phenotype and genotype in iron‐deficient children in the Indian subcontinent. Cases of moderate to severe microcytosis and anaemia with no obvious cause and normal C‐reactive protein, HbA2 and tissue transglutaminase antibody levels (n = 550) were put on a trial of oral iron for 4 weeks. Sixty of these 550 cases (11%) were variably refractory to oral iron therapy (<10 g/l Hb rise) at 4–6 weeks and were subsequently evaluated for plasma iron, ferritin and hepcidin levels. The mean age of this cohort was 2.06 years. Low‐normal to normal ferritin and normal to high hepcidin levels were noted in 25/60 (41.6%) and 47/60 (78.3%), respectively. An IRIDA phenotype was noted in 38.3% (23/60) based on standard criteria. TMPRSS6 gene sequencing in 20 cases with IRIDA phenotype revealed 9 potentially deleterious intronic and two benign exonic variations in 12/20 cases (60%). Of these, 4 intronic and both exonic variations were noted in multiple cases and are likely to act synergistically leading to an IRIDA phenotype. However, given that only 38% (23/60 cases) of cases with iron refractoriness had IRIDA phenotype, a balanced approach is needed and other causes for refractoriness should be investigated before genetic studies for TMPRSS6 are undertaken.
A population-based study of chronic fatigue syndrome (CFS) experienced in differing patient groups: An effort to replicate Vercoulen et al.'s model of CFS

Background: Vercoulen et al.'s (1998) model characterizes patients with chronic fatigue syndrome (CFS) as having insufficient motivation for physical activity or recovery, lacking an internal locus of control, and maintaining a self-defeating preoccupation with symptoms. However, this model has only been tested in a poorly specified group using a single comparison sample. Aims: To investigate whether Vercoulen et al.'s model provides an adequate description of CFS in a community-based sample. Method: A community-based sample recruited through telephone interviewing (N = 28,763) produced five groups (CFS, CF-psychiatrically-explained symptoms, CF-medically-unexplained symptoms, CF-substance misuse, and idiopathic CF). The data were analysed using path analysis with the endogenous (dependent) variables, fatigue severity, physical activity, and impairment, were ratio-level measurements and consisted of at least four values. The exogenous (independent) variables except for causal attribution of fatigue were also ratio-level measurements. Results: The current investigation found that the Vercoulen et al. model adequately represented chronic fatigue secondary to psychiatric conditions but not CFS. Conclusions: This finding points to important differences between CFS and psychiatrically-explained chronic fatigue which may have an impact on the development of therapy as well as explanatory models. Declaration of interest: Financial support for this article was provided by the National Institutes of Allergies and Infectious Diseases grant number AI36295. There are no financial relationships that pose a conflict of interest.
Trafficking in Women in Canada: A Critical Analysis of the Legal Framework Governing Immigrant Live‐in Caregivers

This article will analyze the legal framework for hiring immigrant live‐in caregivers under the Canadian Live‐in Caregiver program. This phenomenon raises issues of immigration law, social legislation and labour law, human rights and contract law. The unequal relationship between an immigrant live‐in caregiver and her employers, the obligation to live in their home for a period of two years, as well as the precariousness of her work status during this period, lead to a situation of abuse. This program contributes to exploitation and trafficking of women in Canada. Thus we propose that this program be discontinued because it allows the exploitation of immigrant workers. However, in order to enable such workers to immigrate to Canada to counteract the shortage of live‐in caregivers, we suggest that the immigration criteria for the independent class be amended.
Predicting the timeline to the final menstrual period: the study of women's health across the nation.

CONTEXT Predicting the final menstrual period (FMP) would help women know when their menopause transition will be completed. Additionally, biological changes, such as accelerated bone loss, precede the FMP by at least 1 year. OBJECTIVE Our objective was to assess whether FSH, estradiol, or urinary N-telopeptide predict where an individual is on her timeline to FMP. METHODS The sample was 554 women from the Study of Women's Health Across the Nation. We modeled the probability of having crossed specified landmarks: 2 years before, 1 year before, and the FMP. We also modeled the probability of being in narrower intervals: 2 to1 year before FMP, 2 years before FMP and FMP, or 1 year before FMP and FMP. We determined the candidate markers that best predicted having crossed each landmark, with the optimum defined as the greatest area under the receiver-operator curve; created formulas for the probability of having crossed each landmark; and calculated sensitivity and specificity. RESULTS Final models included current estradiol and FSH (each as a fraction of 1 previous reference measure), age, menopause transition stage, race/ethnicity, and whether serum was collected during the early follicular phase. Areas under the receiver-operator curves of final models that predicted the probability of a woman having crossed 2 years before, 1 year before, and the FMP itself were 0.902, 0.926, and 0.945, respectively. If we classified women as having crossed the 2 years before the FMP landmark when predicted probability exceeded 0.3, sensitivity was 85% and specificity 77%. CONCLUSION This model could help patients and researchers estimate the time to FMP.
Does addition of BRAF V600E mutation testing modify sensitivity or specificity of the Afirma Gene Expression Classifier in cytologically indeterminate thyroid nodules?

OBJECTIVE The purpose of this study was to determine the frequency of BRAF mutation in cytologically indeterminate thyroid nodules and to investigate whether adding the BRAF test improves diagnostic accuracy of the Afirma Gene Expression Classifier (GEC). DESIGN BRAF V600E mutational status was determined for DNA extracted from cytologically benign (n = 40), indeterminate (n = 208), and malignant (n = 48) fine-needle aspiration specimens previously categorized by GEC as molecularly Benign or Suspicious. Analytical performance of the BRAF assay was assessed to establish reproducibility and limits of detection. Molecular testing results were correlated with blinded expert histopathological diagnoses. RESULTS The BRAF assay detected mutations reproducibly to 2.5% mutant allele frequency. The prevalence of BRAF mutations in cytologically benign specimens was 2 of 40 (5.0%, 95% confidence interval [CI], 0-16) and in cytologically malignant specimens was 36 of 48 (75.0%, 95% CI, 60-86). In the cytologically indeterminate category, 10.1% of specimens were BRAF+: 2 of 95 were subcategorized as atypia of undetermined significance or follicular lesion of undetermined significance (2.1%, 95% CI, 0-7); 1 of 70 as follicular neoplasm or suspicious for follicular neoplasm (1.4%, 95% CI, 0-9); and 18 of 43 as suspicious for malignancy (41.9%, 95% CI, 27-58). All BRAF+ specimens were classified as Suspicious by the GEC. CONCLUSIONS BRAF mutations are uncommon in nodules with atypia of undetermined significance or follicular lesion of undetermined significance or follicular neoplasm or suspicious for follicular neoplasm cytology. Most cytologically indeterminate nodules that proved to be malignant were also BRAF-, and all nodules that were false-negative by GEC were also BRAF-. Similarly, all BRAF+ specimens were also GEC Suspicious. Neither GEC test sensitivity nor specificity was improved by addition of BRAF mutation testing.
Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of 100-299 μg/L: a UNICEF/ICCIDD study group report.

CONTEXT The median urinary iodine concentration (UIC) is a biomarker of iodine intake. According to the World Health Organization, a median UIC in the range 100-199 μg/L indicates adequate and 200-299 μg/L more than adequate intake. Thyroglobulin (Tg) may be a promising functional biomarker of both iodine deficiency and excess. OBJECTIVES Using a standardized dried blood spots-Tg assay in children, we evaluated the Tg response to both low- and high-iodine intake and estimated the population cutoff point for iodine deficiency or excess. Also, we compared thyroid functions within the UIC ranges of 100-199 vs 200-299 μg/L. DESIGN AND SETTING We conducted a cross-sectional study in primary schools in 12 countries. SUBJECTS SUBJECTS were 6 to 12 years old (n = 2512). MAIN OUTCOME MEASURES We measured UIC, TSH, total T4, Tg, and thyroid antibodies. RESULTS Over a range of iodine intakes from severely deficient to excessive, Tg concentrations showed a clear U-shaped curve. Compared with iodine-sufficient children, there was a significantly higher prevalence of elevated Tg values in children with iodine deficiency (UIC <100 μg/L) and iodine excess (UIC >300 μg/L). There was no significant change in the prevalence of elevated Tg, TSH, T4, or thyroid antibodies comparing children within the UIC ranges of 100-199 vs 200-299 μg/L. CONCLUSIONS In school-aged children, 1) Tg is a sensitive indicator of both low and excess iodine intake; 2) a median Tg of <13 μg/L and/or <3% of Tg values >40 μg/L indicates iodine sufficiency in the population; 3) the acceptable range of median UIC in monitoring iodized salt programs could be widened to a single category of sufficient iodine intake from 100 to 299 μg/L.
Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity.

OBJECTIVE Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. METHODS Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. RESULTS Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m² and smallest in women with BMI >30 kg/m². Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. SUMMARY During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.
Advances in predicting venous thromboembolism risk in children

Paediatric venous thromboembolism (VTE) is a rare disorder but a rising incidence has been observed in recent years, due to improved VTE diagnosis and increased use of central venous catheters in the treatment of severe diseases. Risk assessment strategies are well established for adult patients, however, similar guidelines for paediatric patients are largely lacking. Several risk prediction tools have been reported in recent literature, which make use of established risk factors to assess VTE risk in paediatric subgroups, such as hospitalised children, cancer‐diagnosed children and paediatric trauma patients. Although these models suffer several limitations regarding their study size and heterogeneous selection of predictor variables, they offer potential for improving the thromboprophylaxis management in these children. Here, we give an overview on recently reported risk prediction models for paediatric VTE.