Miracle-dz/UniFAR-FTUs huggingface dataset:
Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

BACKGROUND In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5‐year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. METHODS Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. RESULTS In SOFT, the 8‐year disease‐free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8‐year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8‐year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen‐alone group, 31.0% of the tamoxifen–ovarian suppression group, and 32.3% of the exemestane–ovarian suppression group. CONCLUSIONS Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8‐year rates of both disease‐free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen‐alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703, respectively.)
Dlx1 transcription factor regulates dendritic growth and postsynaptic differentiation through inhibition of neuropilin‐2 and PAK3 expression

Dlx1, a member of the homeobox domain transcriptional factors, is expressed in a subset of interneurons and is involved in their differentiation. To understand the roles of Dlx1 in dendritic and postsynaptic differentiation, we manipulated Dlx1 expression in both excitatory pyramidal neurons and inhibitory interneurons in hippocampal culture. Exogenous expression of Dlx1 in pyramidal neurons, which lack endogenous Dlx1, resulted in reduced complexity of dendritic arborization. This effect was dependent on the DNA‐binding motif of Dlx1. Dlx1 overexpression also induced prominent reduction of spine density, but with mild suppression in the formation of postsynaptic densities. To confirm the roles of endogenous Dlx1, we knocked down Dlx1 in interneurons and found enhanced dendritic growth. By manipulating the expression of possible downstream effectors of Dlx1, neuropilin‐2 and p21‐activated kinase 3, we provided evidence for the involvement of these two signaling molecules in Dlx1‐dependent regulation of dendritic differentiation. Our experimental data support the idea that Dlx1 expression in developing interneurons specifically suppresses two important downstream regulators, leading to the characteristic morphology of Dlx1‐expressing interneurons with less branched dendrites and few dendritic spines.
Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors

BACKGROUND Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. METHODS We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. RESULTS A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low‐grade injection‐site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. CONCLUSIONS Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann–La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637.)
Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy

The diuretic bumetanide, which acts by blocking the Na–K–Cl cotransporter (NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N‐butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (PBO) has previously been reported to increase the half‐life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half‐life 47 min vs. 13 min). Pretreatment with PBO increased the half‐life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose‐dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.
Sunitinib Alone or after Nephrectomy in Metastatic Renal‐Cell Carcinoma

BACKGROUND Cytoreductive nephrectomy has been the standard of care in metastatic renal‐cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal‐cell carcinoma who were receiving targeted therapies. METHODS In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear‐cell renal‐cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow‐up was 50.9 months, with 326 deaths observed. The results in the sunitinib‐alone group were noninferior to those in the nephrectomy–sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib‐alone group and 13.9 months in the nephrectomy–sunitinib group. No significant differences in response rate or progression‐free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal‐cell carcinoma who were classified as having intermediate‐risk or poor‐risk disease. (Funded by Assistance Publique–Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033.)
CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model

The medial prefrontal cortex (mPFC) serves executive control functions and forms direct connections with subcortical areas such as the amygdala. Our previous work showed abnormal inhibition of mPFC pyramidal cells and hyperactivity of amygdala output neurons in an arthritis pain model. To restore mPFC activity and hence control pain‐related amygdala hyperactivity this study focused on CB1 and mGluR5 receptors, which are important modulators of cortical functions. Extracellular single‐unit recordings of infralimbic mPFC pyramidal cells and of amygdala output neurons in the laterocapsular division of the central nucleus (CeLC) were made in anesthetised adult male rats. mPFC neurons were classified as ‘excited’ or ‘inhibited’ based on their response to brief innocuous and noxious test stimuli. After arthritis pain induction, background activity and evoked responses of excited neurons and background activity and inhibition of inhibited neurons decreased. Stereotaxic application of an mGluR5‐positive allosteric modulator (N‐cyclobutyl‐6‐((3‐fluorophenyl)ethynyl) nicotinamide hydrochloride, VU0360172) into the mPFC increased background and evoked activity of excited, but not inhibited, mPFC neurons under normal conditions but not in arthritis. A selective CB1 receptor agonist (arachidonyl‐2‐chloroethylamide) alone had no effect but restored the facilitatory effects of VU0360172 in the pain model. Coactivation of CB1 and mGluR5 in the mPFC inhibited the pain‐related activity increase of CeLC neurons but had no effect under normal conditions. The data suggest that excited mPFC neurons are inversely linked to amygdala output (CeLC) and that CB1 can increase mGluR5 function in this subset of mPFC neurons to engage cortical control of abnormally enhanced amygdala output in pain.
C1 Neurons in the RVLM: are they catecholaminergic in name only? (Commentary on Abbott et al.)

Catecholaminergic neurons in the rostral ventrolateral medulla (RVLM), also known as the C1 cell group, are known to play an important role in the generation and control of sympathetic activity (Card et al., 2006). Many of these C1 neurons, as well as neighboring non-catecholaminergic neurons in the RVLM, monosynaptically project to the intermediolateral column of the spinal cord and provide the primary tonic excitatory drive to sympathetic vasomotor and cardiac neurons (Guyenet et al., 2013). RVLM C1 neurons also send projections to many other centers involved in respiratory and autonomic function including the dorsal vagal motor nucleus (DePuy et al., 2013). Here, in this very comprehensive and interesting study conducted by Abbott et al. (2013), the authors crossbred mice to produce progeny in which dopamineb-hydroxylase-containing neurons lacked the glutamate transporter VGLUT2, a transporter responsible for the sequestration of the excitatory neurotransmitter glutamate into synaptic vesicles in these neurons. Furthermore, C1 neurons in these animals could be selectively activated in vivo using optogenetic stimulation of expressed channelrhodopsin-2 (ChR2) following microinjection of a floxed ChR2-expressing virus into the RVLM. Selective photostimulation of the C1 neurons increased respiratory frequency in control animals with unaltered VGLUT2 expression, but in mice with VGLUT2 deficiencies in catecholaminergic neurons the responses upon C1 photoactivation were absent. Similarly, the activation of vagal fibers upon photoactivation of C1 neurons was blunted or absent in animals with VGLUT2 deficiencies. This work, taken together with previous work from this group and others, indicates that catecholaminergic neurons in the RVLM use glutamate primarily, if not exclusively, as a transmitter to influence downstream autonomic and respiratory neurons (Morrison, 2003; Guyenet et al., 2013). This well-founded conclusion raises the issue, are these neurons catecholaminergic in name only? Three potential unexplored roles for catecholamine synthesis in these neurons are that catecholamines are co-released from the synapses of these neurons but do not act on their anticipated postsynaptic neuronal targets but rather alter glial or other non-neuronal targets. Alternatively, catecholamines might only be synaptically co-released from these neurons upon challenges to the autonomic and/or respiratory systems or in disease states. This, while possible, seems unlikely as these investigators stimulated C1 neurons with a range of activation paradigms. Another interesting and yet untested hypothesis is that catecholamines are released not at the synapse but at the soma or dendrites of C1 neurons to serve in a role distinctly different from fast neurotransmission (Sevigny et al., 2008). This important study demonstrates the powerful influence of the glutamatergic projections of these C1 neurons on respiratory and autonomic function, but why they are catecholaminergic remains unknown.
Functional connectivity‐based parcellation of the human sensorimotor cortex

Task‐based functional magnetic resonance imaging (fMRI) has been successfully employed to obtain somatotopic maps of the human sensorimotor cortex. Here, we showed through direct comparison that a similar functional map can be obtained, independently of a task, by performing a connectivity‐based parcellation of the sensorimotor cortex based on resting‐state fMRI. Cortex corresponding to two adjacent Brodmann areas (BA 3 and BA 4) was selected as the sensorimotor area. Parcellation was obtained along a medial–lateral axis, which was confirmed to be somatotopic (corresponding roughly to an upper, middle and lower limb, respectively) by comparing it with maps obtained using motoric task‐based fMRI in the same participants. Interestingly, the resting‐state parcellation map demonstrated higher correspondence to the task‐based divisions after individuals performed the motor task. Using the resting‐state fMRI data, we also observed higher functional correlations between the centrally located hand region and the other two regions, than between the foot and tongue. The functional relevance of these somatosensory parcellation results indicates the feasibility of a wide range of potential applications to brain mapping.
Coronary CT Angiography and 5‐Year Risk of Myocardial Infarction

BACKGROUND Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5‐year clinical outcomes is unknown. METHODS In an open‐label, multicenter, parallel‐group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow‐up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. RESULTS The median duration of follow‐up was 4.8 years, which yielded 20,254 patient‐years of follow‐up. The 5‐year rate of the primary end point was lower in the CTA group than in the standard‐care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard‐care group in the first few months of follow‐up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard‐care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard‐care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between‐group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause. CONCLUSIONS In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT‐HEART ClinicalTrials.gov number, NCT01149590.)
Health care reform requires accountable care systems.

is targeted. Many clinically proven interventions are relatively cost-effectivebutnotcost savingandmayaffectonlysmallportions of an overall population, and some clinically effective interventionsdonothavepositiveratesofreturnasinvestments. Also,manynonfinancialbarriers tohealth improvementmust beovercomeandothernonhealthproblemsmustbeaddressed forhealtheffects to translate intoeconomicgain.Theoutcome dependsonthepolitical commitment to improvinghealth, the political and policy decisions that are made, and the prioritization of needs and deployment of resources within a society. What is important is that the roleofhealthasaproductiveeconomic investment be captured and that focused efforts to improvehealthshouldbepartof theeconomicdevelopmentplan.
The reactions of the family companion of hospitalized elderly facing stressful situations

Objetivos : Caracterizar o familiar acompanhante de idosos hospitalizados; descrever as reacoes do familiar acompanhante de idosos hospitalizados frente as situacoes de estresse e discutir as possibilidades de intervencao do enfermeiro ao familiar acompanhante desses idosos. Metodo: Estudo qualitativo, descritivo e exploratorio. Realizad o em enfermarias de um hospital geral com 45 familiares acompanhantes de idosos hospitalizados. Foi realizada entrevista semi-estruturada e os dados foram submetidos a analise tematica. O estudo teve aprovacao do comite de etica. Resultados: As principais reacoes frente as situacoes de estresse: alteracoes nos habitos alimentares, utilizacao de medicamentos para relaxamento e insonia e mudancas de humor. Para o enfrentamento das situacoes de estresse buscam atividades alternativas de lazer e apego as praticas religiosas. Conclusao: o familiar acompanhante de idosos deve tambem ser foco de cuidado da enfermagem durante o processo de hospitalizacao, mediante estrategias de suporte e programas educativos para preservar sua saude.
Brigatinib versus Crizotinib in ALK‐Positive Non–Small‐Cell Lung Cancer

Background Brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK‐positive non–small‐cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK‐positive NSCLC who have not previously received an ALK inhibitor is unclear. Methods In an open‐label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK‐positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7‐day lead‐in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression‐free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. Results A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow‐up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression‐free survival was higher with brigatinib than with crizotinib (estimated 12‐month progression‐free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log‐rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. Conclusions Among patients with ALK‐positive NSCLC who had not previously received an ALK inhibitor, progression‐free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA‐1L ClinicalTrials.gov number, NCT02737501.)