Miracle-dz/UniFAR-FTUs huggingface dataset:
A capacitor-less low-dropout regulator for SoC with bi-directional asymmetric buffer

1.0-V, 50-mA capacitor-less low-dropout (LDO) voltage regulator with 100pF internal output capacitor for SoC applications is presented. The proposed LDO makes use of a bi-directional asymmetric buffer (BDAB), which provides a signal inversion feedback path and a signal non-inversion feedforward path with different magnitudes at the same time. The feedback path can perform frequency compensation and transient enhancement, while the feedforward path can improve the stability and increase the unit-gain frequency (UGF) by removing right-half-plane (RHP) zero. Simulation results show that the LDO has robust stability, high UGF (up to 1.7-MHz even at no-load), and excellent transient response performance. The overshoot and undershoot of the output voltages are less than 100-mV when the load step changes between 0 and 50-mA in 1-mus, the settling time is 2-mus, while the dropout voltage is 100-mV at full-load current.
Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Abstract Objectives: Luseogliflozin is a selective sodium glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). This phase II study was conducted to confirm the efficacy and safety of luseogliflozin monotherapy at doses of up to 10 mg in Japanese patients with T2DM. Patients and methods: Patients with hemoglobin A1c (HbA1c) of 6.9–10.5% on diet therapy were randomized in a double-blind manner to treatment with 1, 2.5, 5, or 10 mg luseogliflozin or placebo for 12 weeks (n = 56, 56, 54, 58, and 58, respectively). Trial registration: Japan Pharmaceutical Information Center (identifier: Japic CTI-101191). Main outcome measures: The primary endpoint was the change in HbA1c from baseline to the end of treatment. Other endpoints included fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight. Adverse events were recorded throughout the study. Results: HbA1c decreased significantly at the end of treatment in the 1, 2.5, 5, and 10 mg luseogliflozin groups compared with placebo (−0.29, −0.39, −0.46, and −0.43%, respectively, versus +0.22%; all P < 0.001), as did FPG and PPG (all P < 0.001). Body weight also decreased significantly in all luseogliflozin groups compared with placebo (all P < 0.001). The incidence rates of adverse events (40.0–50.0%) were not significantly different among the five groups. The overall incidence of hypoglycemia was low. Limitations of this study include the short study duration and the relatively small sample size. Conclusions: In Japanese patients with T2DM, luseogliflozin was well tolerated, improved glycemic control, and reduced body weight over 12 weeks of treatment at all tested doses. Doses of ≥2.5 mg achieved similar improvements in glycemic control.
Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer

Objective Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. Design Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). Results Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. Conclusion This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex

To investigate the effects of light therapy on serotonin transporter binding (5‐HTT BPND), an index of 5‐HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty‐five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5‐HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5‐HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5‐HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation.
Proton pump inhibitor use associated with changes in gut microbiota composition

We read with great interest the recent publications in Gut by Imhann et al and Jackson et al , which assessed the impact of proton pump inhibitor (PPI) use on gut microbiota diversity and composition in humans.1 2 PPIs are one of the most commonly used drug classes worldwide. Once initiated, they are often used chronically without clear therapeutic intent.3 PPIs alter GI pH4 and delay gastric emptying rate,5 which could directly affect gut microbiota and survival of enteric pathogens. Using three independent cohorts (211 PPI users and 1604 non-users), Imhann et al 1 reported a significant decrease in alpha diversity and changes in 20% of bacterial taxa in PPI users compared with non-users. Among 1827 healthy twins, Jackson et al 2 also found a significant decrease in alpha diversity and alteration of bacterial composition in PPI users. Notably, both studies found a higher abundance of oral commensals, including Streptococcaceae …
Impact of fatigue on outcome of selective serotonin reuptake inhibitor treatment: secondary analysis of STAR*D

Abstract Objective: To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy. Research design and methods: Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (≤14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16; scored 0–3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue). Clinical trial registration: Http://clinicaltrials.gov, NCT00021528. Main outcome measures: Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression ≤7 or QIDS-SR16 ≤5); Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS). Results: At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment-emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P < 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P < 0.0001), and reduced mental and physical function at outcome (P ≤ 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P < 0.0001), indicative of more severe functional impairment. Conclusions: Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post-hoc analysis design.
Non-superiority of lumen-apposing metal stents over plastic stents for drainage of walled-off necrosis in a randomised trial

Objective Although lumen-apposing metal stents (LAMS) are increasingly used for drainage of walled-off necrosis (WON), their advantage over plastic stents is unclear. We compared efficacy of LAMS and plastic stents for WON drainage. Design Patients with WON were randomised to endoscopic ultrasound-guided drainage using LAMS or plastic stents. Primary outcome was comparing total number of procedures to achieve treatment success defined as symptom relief in conjunction with WON resolution on CT at 6 months. Secondary outcomes were treatment success, procedure duration, clinical/stent-related adverse events, readmissions, length of hospital stay (LOS) and costs. Results 60 patients underwent LAMS (n=31) or plastic stent (n=29) placement. There was no significant difference in total number of procedures performed (median 2 (range 2–7) LAMS vs 3 (range 2–7) plastic, p=0.192), treatment success, clinical adverse events, readmissions, LOS and overall treatment costs between cohorts. Although procedure duration was shorter (15 vs 40 min, p<0.001), stent-related adverse events (32.3% vs 6.9%, p=0.01) and procedure costs (US$12 155 vs US$6609, p<0.001) were higher with LAMS. Significant stent-related adverse events were observed ≥3 weeks postintervention in LAMS cohort. Interim audit resulted in protocol amendment where CT scan was obtained at 3 weeks postintervention followed by LAMS removal if WON had resolved. After protocol amendment, there was no significant difference in adverse events between cohorts. Conclusion Except for procedure duration, there was no significant difference in treatment outcomes between LAMS and plastic stents. To minimise adverse events with LAMS, patients should undergo follow-up imaging and stent removal at 3 weeks if WON has resolved. Trial registration number NCT02685865.
Structural brain aberrations associated with the dissociative subtype of post‐traumatic stress disorder

One factor potentially contributing to the heterogeneity of previous results on structural grey matter alterations in adult participants suffering from post‐traumatic stress disorder (PTSD) is the varying levels of dissociative symptomatology. The aim of this study was therefore to test whether the recently defined dissociative subtype of PTSD characterized by symptoms of depersonalization and derealization is characterized by specific differences in volumetric brain morphology.
Protocol registration and selective outcome reporting in recent psychiatry trials: new antidepressants and cognitive behavioural therapies

The selective reporting of favorable outcomes has a serious influence on our evidence base. However, this problem has not yet been systematically investigated in the field of psychiatry. Our study aimed to evaluate registration and outcome reporting in randomized controlled trials (RCTs) of standard treatments for depression: cognitive behavioural therapy (CBT) or new‐generation antidepressants (ADs).
PANSS‐6: a brief rating scale for the measurement of severity in schizophrenia

The 30‐item Positive and Negative Syndrome Scale (PANSS‐30) is the most widely used rating scale in schizophrenia, but too long for clinical use. Shorter PANSS versions have been proposed, including the PANSS‐14 and PANSS‐8. However, none of these PANSS versions has been validated using the parametric Rasch rating scale model, which evaluates ‘scalability’. Scalability means that each item in a rating scale provides unique information regarding syndrome severity and is a statistical prerequisite for using the total score as a measure of overall severity.
A2.15 Relative Overexpression of Transmembrane Versus Soluble TNF in Human and Experimental Spondyloarthritis

Background Macrophages and their pro-inflammatory cytokines, including TNF, are pivotal mediators of chronic synovitis in rheumatoid arthritis (RA) as well as spondyloarthritis (SpA). Despite similar levels of synovial macrophage infiltration and similar clinical responses to TNF blockade in both diseases, SpA is characterised by a more pronounced infiltration with alternatively activated CD163+ macrophages and ongoing osteoproliferation. This study aimed to investigate whether these differences were related to a differential expression and/or function of TNF between both diseases. Methods Expression of transmembrane TNF (tmTNF) and soluble TNF (sTNF) was measured in IFN-γ, IL-4 or IL-10 polarised macrophages obtained from healthy donors. Expression of TNF and its receptors was measured in synovial fluid (SF) and synovial tissue biopsies (ST) of actively inflamed knee joints of SpA and RA patients. Mice transgenically overexpressing tmTNF (TgA86) were evaluated for spondylitis and arthritis. Results In vitro polarisation with IL-10 specifically induced the expression of CD163 on macrophages, mimicking the phenotype in SpA synovitis. IL-10 and IL-4 polarised macrophages secreted less TNF than classically, IFN-γ-polarised macrophages (p < 0.05). In contrast, IL-4 polarised macrophages expressed more tmTNF compared to the IFN-γ polarised macrophages (p < 0.05), with a similar trend for IL-10 polarised macrophages. In line with these in vitro data, the sTNF SF levels were significantly lower in SpA compared to RA (p = 0.01) despite similar TNF mRNA levels in ST. This was not related to higher expression of TNF receptors as both TNFR1 and TNFR2 were similarly expressed in ST, both at protein and mRNA levels. On the contrary, the SF levels of sTNFR1 and sTNFR2, which are both cleaved from the cell membrane by the same enzyme as tmTNF, were even decreased in SpA versus RA. Investigating the potential pathophysiological role of relative overexpression of tmTNF versus sTNF in vivo, clinical analysis revealed that tmTNF transgenic mice developed arthritis, resulting in deformation and loss of grip strength, and spondylitis as evidenced by crinkled tails with a 100% incidence. Axial and peripheral joint inflammation was confirmed by histology. In contrast to mouse strains overexpressing sTNF, tmTNF tg mice did not develop systemic disease and weight loss and showed clear signs of osteoproliferation on histology. Conclusions tmTNF is relatively overexpressed by CD163+ alternatively polarised macrophages in SpA synovitis and leads to an axial and peripheral SpA phenotype in transgenic mice.
Areas suspicious for prostate cancer: MR-guided biopsy in patients with at least one transrectal US-guided biopsy with a negative finding--multiparametric MR imaging for detection and biopsy planning.

PURPOSE To prospectively investigate the incremental value of multiparametric magnetic resonance (MR) imaging compared with standard T2-weighted imaging for biopsy planning. MATERIALS AND METHODS The study was approved by the institutional review board; informed consent was obtained. Consecutive patients underwent T2-weighted imaging supplemented with multiparametric 1.5-T MR imaging, consisting of hydrogen 1 ((1)H) MR spectroscopy, diffusion-weighted (DW) imaging, and contrast material-enhanced MR imaging. Quantitative parameters were calculated: (choline plus creatine)-to-citrate ratio, apparent diffusion coefficient, and volume transfer constant and exchange rate constant. The prostate was divided into 20 standardized areas. Each area was classified as benign, inconclusive, or suspicious at T2-weighted imaging, followed by quantitative evaluation of all inconclusive and suspicious areas with multiparametric MR imaging. MR-guided biopsy was performed in lesions classified as suspicious for cancer with at least one of the techniques after transfer to three-dimensional T2-weighted images. Diagnostic parameters were calculated on a per-lesion and per-patient basis for all combinations of T2-weighted imaging with multiparametric MR imaging. RESULTS Fifty-four patients had a median of two prior transrectal ultrasonographic biopsies with negative findings. Each patient had a median of three suspicious lesions. Prostate cancer was demonstrated in 21 of 54 patients. Biopsy was performed in 178 lesions; 53 were positive for prostate cancer. Detection rates and test negative results, respectively, were as follows: T2-weighted imaging, 70% and 50%; T2-weighted imaging and (1)H MR spectroscopy, 81% and 32%; T2-weighted imaging and contrast-enhanced MR imaging, 83% and 29%; T2-weighted imaging and DW imaging, 85% and 30%; T2-weighted imaging, (1)H MR spectroscopy, and contrast-enhanced MR imaging, 91% and 13%; T2-weighted imaging, (1)H MR spectroscopy, and DW imaging, 94% and 15%; T2-weighted imaging, DW imaging, and contrast-enhanced MR imaging, 94% and 13%; T2-weighted imaging, (1)H MR spectroscopy, DW imaging, and contrast-enhanced MR imaging, 100% and 0%. CONCLUSION Only the combination of T2-weighted imaging with all three multiparametric techniques depicts all identifiable prostate cancers; a double combination with DW imaging and (1)H MR spectroscopy or contrast-enhanced MR imaging misses 6%, while reasonably reducing the number of areas needing biopsy.
RDoC is adverse to scientific creativity

In their large observational study, Vanasse et al. showed that clozapine was more effective than other antipsychotics with regard to real-world clinical outcomes (i.e., suicide, hospitalization, and emergency department visit for mental disorders). Their finding is in line with existing experimental and observational evidence that supports the current status of clozapine as the gold standard treatment for refractory schizophrenia. This study is published simultaneously with two metaanalyses of blinded randomized clinical trials, that reported considerably contradictory findings in terms of the efficacy of clozapine in comparison with other second-generation antipsychotic drugs. The two meta-analyses used different methodologies, albeit they were both robustly conducted and conformed to the PRISMA statement standards. This paradox could be perplexing and misleading to busy clinicians who wish to maintain an up-to-date evidence-informed practice. It has been demonstrated that meta-analyses could be inherently fundamentally compromised by their intertrial heterogeneity and methodological inconsistencies, thus questioning their current placement at the top of evidence-based medicine pyramid. To a practicing clinician, an average effect size of clozapine treatment across thousands of highly heterogeneous patients is far less meaningful than narrative critical reviews of individual studies that enable extrapolation to realworld clinical practice. Declaration of interest
DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Background and aims Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis. Design We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity. Results We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling. Conclusions These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
Pregnancy and fertility following bariatric surgery: a systematic review.

CONTEXT Use of bariatric surgery has increased dramatically during the past 10 years, particularly among women of reproductive age. OBJECTIVES To estimate bariatric surgery rates among women aged 18 to 45 years and to assess the published literature on pregnancy outcomes and fertility after surgery. EVIDENCE ACQUISITION Search of the Nationwide Inpatient Sample (1998-2005) and multiple electronic databases (Medline, EMBASE, Controlled Clinical Trials Register Database, and the Cochrane Database of Reviews of Effectiveness) to identify articles published between 1985 and February 2008 on bariatric surgery among women of reproductive age. Search terms included bariatric procedures, fertility, contraception, pregnancy, and nutritional deficiencies. Information was abstracted about study design, fertility, and nutritional, neonatal, and pregnancy outcomes after surgery. EVIDENCE SYNTHESIS Of 260 screened articles, 75 were included. Women aged 18 to 45 years accounted for 49% of all patients undergoing bariatric surgery (>50,000 cases annually for the 3 most recent years). Three matched cohort studies showed lower maternal complication rates after bariatric surgery than in obese women without bariatric surgery, or rates approaching those of nonobese controls. In 1 matched cohort study that compared maternal complication rates in women after laparoscopic adjustable gastric band surgery with obese women without surgery, rates of gestational diabetes (0% vs 22.1%, P < .05) and preeclampsia (0% vs 3.1%, P < .05) were lower in the bariatric surgery group. Findings were supported by 13 other bariatric cohort studies. Neonatal outcomes were similar or better after surgery compared with obese women without laparoscopic adjustable gastric band surgery (7.7% vs 7.1% for premature delivery; 7.7% vs 10.6% for low birth weight, P < .05; 7.7% vs 14.6% for macrosomia, P < .05). No differences in neonatal outcomes were found after gastric bypass compared with nonobese controls (26.3%-26.9% vs 22.4%-20.2% for premature delivery, P = not reported [1 study] and P = .43 [1 study]; 7.7% vs 9.0% for low birth weight, P = not reported [1 study]; and 0% vs 2.6%-4.3% for macrosomia, P = not reported [1 study] and P = .28 [1 study]). Findings were supported by 10 other studies. Studies regarding nutrition, fertility, cesarean delivery, and contraception were limited. CONCLUSION Rates of many adverse maternal and neonatal outcomes may be lower in women who become pregnant after having had bariatric surgery compared with rates in pregnant women who are obese; however, further data are needed from rigorously designed studies.