Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.

BACKGROUND Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
Early Sedation with Dexmedetomidine in Critically Ill Patients.

BACKGROUND Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied. METHODS In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 [unresponsive] to +4 [combative]) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days. RESULTS We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group. CONCLUSIONS Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.).
Downregulation of Centaurin gamma1A increases synaptic transmission at Drosophila larval neuromuscular junctions

Adequate regulation of synaptic transmission is critical for appropriate neural circuit functioning. Although a number of molecules involved in synaptic neurotransmission have been identified, the molecular mechanisms regulating neurotransmission are not fully understood. Here, we focused on Centaurin gamma1A (CenG1A) and examined its role in synaptic transmission regulation using Drosophila larval neuromuscular junctions. CenG1A is a member of the Centaurin family, which contains Pleckstrin homology, ADP ribosylation factor GTPase‐activating protein, and ankyrin repeat domains. Due to the existence of these functional domains, CenG1A is proposed to be involved in the process of synaptic release; however, no evidence for this has been found to date. In this study, we investigated the potential role for CenG1A in the process of synaptic release by performing intracellular recordings in larval muscle cells. We found that neurotransmitter release from presynaptic cells was enhanced in cenG1A mutants. This effect was also observed in larvae with reduced CenG1A function in either presynaptic or postsynaptic cells. In addition, we revealed that suppressing CenG1A function in postsynaptic muscle cells led to an increase in the probability of neurotransmitter release, whereas its suppression in presynaptic neurons led to an increase in neurotransmitter release probability and an increase in the number of synaptic vesicles. These results suggested that CenG1A functions at both presynaptic and postsynaptic sites as a negative regulator of neurotransmitter release. Our study provided evidence for a key role of CenG1A in proper synaptic transmission at neuromuscular junctions.
Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3

Polyglutamine (polyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration in Spinocerebellar Ataxia Type 3 (SCA3), one of nine inherited, incurable diseases caused by similar mutations. Ataxin-3's degradation is inhibited by its binding to the proteasome shuttle Rad23 through ubiquitin-binding site 2 (UbS2). Disrupting this interaction decreases levels of ataxin-3. Since reducing levels of polyQ proteins can decrease their toxicity, we tested whether genetically modulating the ataxin-3-Rad23 interaction regulates its toxicity in Drosophila. We found that exogenous Rad23 increases the toxicity of pathogenic ataxin-3, coincident with increased levels of the disease protein. Conversely, reducing Rad23 levels alleviates toxicity in this SCA3 model. Unexpectedly, pathogenic ataxin-3 with a mutated Rad23-binding site at UbS2, despite being present at markedly lower levels, proved to be more pathogenic than a disease-causing counterpart with intact UbS2. Additional studies established that the increased toxicity upon mutating UbS2 stems from disrupting the autoprotective role that pathogenic ataxin-3 has against itself, which depends on the co-chaperone, DnaJ-1. Our data reveal a previously unrecognized balance between pathogenic and potentially therapeutic properties of the ataxin-3-Rad23 interaction; they highlight this interaction as critical for the toxicity of the SCA3 protein, and emphasize the importance of considering protein context when pursuing suppressive avenues.
A frequent oligogenic involvement in congenital hypothyroidism.

Congenital hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in <10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects. Non-synonymous or splicing rare variants (MAF < 0.01) were accepted, and their functional impact was predicted by a comprehensive bioinformatic approach and co-segregation studies. The frequency of variations in cases and controls was extended to 18 CH-unrelated genes. At least one rare variant was accepted in 103/177 patients. Monogenic recessive forms of the disease were found in five cases, but oligogenic involvement was detected in 39 patients. The 167 variations were found to affect all genes independently of the CH phenotype. These findings were replicated in an independent cohort of additional 145 CH cases. When compared to 3,538 controls, the CH population was significantly enriched with disrupting variants in the candidate genes (P = 5.5 × 10-7), but not with rare variations in CH-unrelated genes. Co-segregation studies of the hypothyroid phenotype with multiple gene variants in several pedigrees confirmed the potential oligogenic origin of CH. The systematic NGS approach reveals the frequent combination of rare variations in morphogenetic or functional candidate genes in CH patients independently of phenotype. The oligogenic origin represents a suitable explanation for the frequent sporadic CH occurrence.
Meaning in the avian auditory cortex: neural representation of communication calls

Understanding how the brain extracts the behavioral meaning carried by specific vocalization types that can be emitted by various vocalizers and in different conditions is a central question in auditory research. This semantic categorization is a fundamental process required for acoustic communication, and presupposes discriminative and invariance properties of the auditory system for conspecific vocalizations. Songbirds have been used extensively to study vocal learning, but the communicative function of all their vocalizations and their neural representation has yet to be examined. In this study, we first generated a library containing almost the entire zebra finch vocal repertoire, and organised communication calls along nine different categories according to their behavioral meaning. We then investigated the neural representations of these semantic categories in the primary and secondary auditory areas of six anesthetised zebra finches. To analyse how single units encode these call categories, we described neural responses in terms of their discrimination, selectivity and invariance properties. Quantitative measures for these neural properties were obtained with an optimal decoder using both spike counts and spike patterns. Information theoretic metrics show that almost half of the single units encode semantic information. Neurons achieve higher discrimination of these semantic categories by being more selective and more invariant. These results demonstrate that computations necessary for semantic categorization of meaningful vocalizations are already present in the auditory cortex, and emphasise the value of a neuro‐ethological approach to understand vocal communication.
Off the record--avoiding the pitfalls of going electronic.

The ultimate goal of the electronic medical record is to make all patient information immediately accessible and easily transferable and to allow its essential elements to be held by both physician and patient. Drs. Pamela Hartzband and Jerome Groopman write that before blindly embracing electronic records, we should consider their current limitations and potential downsides.
Communication practices among nurses in the acute care setting

Abstract Aim To describe and quantify nursing communication practices in the in-patient setting. Background Strategies aimed at improving communication among the healthcare team have resulted in marginal improvements, which may in part be due to the limited time the team communicates with one another. Method Nurses (n = 12) on three different types of units were observed to determine time spent in synchronous communication with the healthcare team. Results Total communication time, on average, was 2.85 hours (23.8%) of a 12-hour shift, with nurse–physician communication (11.3 minutes) and nurse-assistive personnel (8.5 minutes) accounting for a small part of time. Differences in time communicating with physicians were noted between the intensive care unit and the pediatric unit. Time spent in communication with unlicensed assistive personnel was 9.6 minutes in the intensive care unit, 14.1 minutes in the adult unit, and only 1.8 minutes in the pediatric unit. Conclusion Strategies must be identified that will either maximize time spent in communication or provide more opportunities for communication to occur. Administrators must reinforce the need for communication and initiate opportunities for engagement among the team. They must role model the importance of communicating with all members of the healthcare team, as well as instill the importance of time spent in communication.
Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila

Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms of familial Parkinson's disease (PD). However, the physiological and pathological roles of Vps35 and LRRK2 in neuronal functions are poorly understood. Here, we demonstrated that the loss of Drosophila Vps35 (dVps35) affects synaptic vesicle recycling, dopaminergic synaptic release and sleep behavior associated with dopaminergic activity, which is rescued by the expression of wild-type dVps35 but not the PD-associated mutant dVps35 D647N. Drosophila LRRK2 dLRRK together with Rab5 and Rab11 is also implicated in synaptic vesicle recycling, and the manipulation of these activities improves the Vps35 synaptic phenotypes. These findings indicate that defects of synaptic vesicle recycling in which two late-onset PD genes, Vps35 and LRRK2, are involved could be key aspects of PD etiology.
Pupil size tracks perceptual content and surprise

Changes in pupil size at constant light levels reflect the activity of neuromodulatory brainstem centers that control global brain state. These endogenously driven pupil dynamics can be synchronized with cognitive acts. For example, the pupil dilates during the spontaneous switches of perception of a constant sensory input in bistable perceptual illusions. It is unknown whether this pupil dilation only indicates the occurrence of perceptual switches, or also their content. Here, we measured pupil diameter in human subjects reporting the subjective disappearance and re‐appearance of a physically constant visual target surrounded by a moving pattern (‘motion‐induced blindness’ illusion). We show that the pupil dilates during the perceptual switches in the illusion and a stimulus‐evoked ‘replay’ of that illusion. Critically, the switch‐related pupil dilation encodes perceptual content, with larger amplitude for disappearance than re‐appearance. This difference in pupil response amplitude enables prediction of the type of report (disappearance vs. re‐appearance) on individual switches (receiver‐operating characteristic: 61%). The amplitude difference is independent of the relative durations of target‐visible and target‐invisible intervals and subjects' overt behavioral report of the perceptual switches. Further, we show that pupil dilation during the replay also scales with the level of surprise about the timing of switches, but there is no evidence for an interaction between the effects of surprise and perceptual content on the pupil response. Taken together, our results suggest that pupil‐linked brain systems track both the content of, and surprise about, perceptual events.
Guías de diagnóstico y tratamiento del estreñimiento en México. D) Evaluación y tratamiento del estreñimiento en población pediátrica

BACKGROUND Constipation is one of the most common causes of consultation in pediatric practice, it has a multifactorial etiology and its treatment can be complex. OBJECTIVES AND METHODS To establish the clinical guidelines for diagnosis and treatment of chronic constipation in pediatric population in Mexico, a review of the epidemiological, diagnostic and therapeutic aspects was conducted by an expert group of pediatric gastroenterologist in our country. RESULTS Constipation is a symptom that reflects the presence of fecal retention, which is reported by patients or their relatives as decreased stool frequency, hard stools, and sometimes pain and excessive pushing. Constipation can occur at any stage of childhood. The main trigger for fecal retention is the painful evacuation. Patients who meet the Rome III criteria for functional constipation do not require diagnostic tests. The diagnostic tests are reserved for cases in which alarm signs are present and in patients refractory to conventional treatment. The goal of treatment is to promote smooth and painless evacuations preventing reaccumulation of stool. Osmotic laxatives such as polyethylene glycol and lactulose are the most effective treatments. In special cases, biofeedback therapy, the use of botulinum toxin and surgery can be effective, although the evidence is weak. CONCLUSIONS Management of chronic constipation in pediatric population requires a comprehensive diagnostic approach.
The effects of long-term administration of bovine growth hormone on the lactational performance of identical-twin dairy cows

The effect of chronic administration of bovine growth hormone (GH) on milk production, food intake and live-weight change was evaluated in five sets of monozygotic twin cows on pasture. Purified bovine pituitary GH (specific activity, 0·78 IU/mg) was administered by daily subcutaneous injections (39 IU/day) for a period of 22 weeks (weeks 5 to 26 of lactation). GH treatment resulted in significantly higher yields of milk (23·3 kg/day), fat (0·97 kg/day), protein (0·74 kg/day) and lactose (115 kg/day) compared with the control group (19·8 kg/day, 0·79 kg/day, 0·63 kg/day, 0·99 kg/day). Milk composition did not differ between treatment groups. There was no difference in the intake of cut grass in week 8 but the voluntary intake of the GH group had increased by week 22 (controls, 15·4 kg dry matter (DM) per day and GH group, 17·5 kg DM per day). There were no differences in the rate of live-weight change for the two groups. Serum somatomedin concentrations were significantly elevated in the GH group on weeks 20 to 22 of treatment (0·043 v . 0·135 U/ml). This experiment indicates that cows chronically treated with GH were able to adjust their food intake upwards to sustain a substantial increase in milk production on a diet composed solely of grass.
Medicare nonpayment, hospital falls, and unintended consequences.

Medicare will no longer reimburse hospitals for a higher-paying diagnosis-related group when one of eight selected hospital-acquired conditions develops during the hospital stay. Drs. Sharon Inouye, Cynthia Brown, and Mary Tinetti write that the inclusion of hospital falls and trauma may cause greater harm than the falls that the initiative is meant to prevent.
Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

Root avulsions due to traction to the brachial plexus causes complete and permanent loss of function. Until fairly recent, such lesions were considered impossible to repair. Here we review clinical repair strategies and current progress in experimental ventral root avulsion lesions. The current gold standard in patients with a root avulsion is nerve transfer, whereas reimplantation of the avulsed root into the spinal cord has been performed in a limited number of cases. These neurosurgical repair strategies have significant benefit for the patient but functional recovery remains incomplete. Developing new ways to improve the functional outcome of neurosurgical repair is therefore essential. In the laboratory, the molecular and cellular changes following ventral root avulsion and the efficacy of intervention strategies have been studied at the level of spinal motoneurons, the ventral spinal root and peripheral nerve, and the skeletal muscle. We present an overview of cell‐based pharmacological and neurotrophic factor treatment approaches that have been applied in combination with surgical reimplantation. These interventions all demonstrate neuroprotective effects on avulsed motoneurons, often accompanied with various degrees of axonal regeneration. However, effects on survival are usually transient and robust axon regeneration over long distances has as yet not been achieved. Key future areas of research include finding ways to further extend the post‐lesion survival period of motoneurons, the identification of neuron‐intrinsic factors which can promote persistent and long‐distance axon regeneration, and finally prolonging the pro‐regenerative state of Schwann cells in the distal nerve.
Seasonal Influenza Infections and Cardiovascular Disease Mortality.

IMPORTANCE Cardiovascular deaths and influenza epidemics peak during winter in temperate regions. OBJECTIVES To quantify the temporal association between population increases in seasonal influenza infections and mortality due to cardiovascular causes and to test if influenza incidence indicators are predictive of cardiovascular mortality during the influenza season. DESIGN, SETTING, AND PARTICIPANTS Time-series analysis of vital statistics records and emergency department visits in New York City, among cardiovascular deaths that occurred during influenza seasons between January 1, 2006, and December 31, 2012. The 2009 novel influenza A(H1N1) pandemic period was excluded from temporal analyses. EXPOSURES Emergency department visits for influenza-like illness, grouped by age (≥0 years and ≥65 years) and scaled by laboratory surveillance data for viral types and subtypes, in the previous 28 days. MAIN OUTCOMES AND MEASURES Mortality due to cardiovascular disease, ischemic heart disease, and myocardial infarction. RESULTS Among adults 65 years and older, who accounted for 83.0% (73 363 deaths) of nonpandemic cardiovascular mortality during influenza seasons, seasonal average influenza incidence was correlated year to year with excess cardiovascular mortality (Pearson correlation coefficients ≥0.75, P ≤ .05 for 4 different influenza indicators). In daily time-series analyses using 4 different influenza metrics, interquartile range increases in influenza incidence during the previous 21 days were associated with an increase between 2.3% (95% CI, 0.7%-3.9%) and 6.3% (95% CI, 3.7%-8.9%) for cardiovascular disease mortality and between 2.4% (95% CI, 1.1%-3.6%) and 6.9% (95% CI, 4.0%-9.9%) for ischemic heart disease mortality among adults 65 years and older. The associations were most acute and strongest for myocardial infarction mortality, with each interquartile range increase in influenza incidence during the previous 14 days associated with mortality increases between 5.8% (95% CI, 2.5%-9.1%) and 13.1% (95% CI, 5.3%-20.9%). Out-of-sample prediction of cardiovascular mortality among adults 65 years and older during the 2009-2010 influenza season yielded average estimates with 94.0% accuracy using 4 different influenza metrics. CONCLUSIONS AND RELEVANCE Emergency department visits for influenza-like illness were associated with and predictive of cardiovascular disease mortality. Retrospective estimation of influenza-attributable cardiovascular mortality burden combined with accurate and reliable influenza forecasts could predict the timing and burden of seasonal increases in cardiovascular mortality.