Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts

Are Long-Range Structural Correlations Behind the Aggregration Phenomena of Polyglutamine Diseases?

We have characterized the conformational ensembles of polyglutamine peptides of various lengths (ranging from to ), both with and without the presence of a C-terminal polyproline hexapeptide. For this, we used state-of-the-art molecular dynamics simulations combined with a novel statistical analysis to characterize the various properties of the backbone dihedral angles and secondary structural motifs of the glutamine residues. For (i.e., just above the pathological length for Huntington's disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible -helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including - and -strands, and - and -hairpins. Most importantly, for we find that there exists a long-range correlation (ranging for at least residues) among the backbone dihedral angles of the Q residues. For polyglutamine peptides below the pathological length, the population of the extended strands and hairpins is considerably smaller, and the correlations are short-range (at most residues apart). Adding a C-terminal hexaproline to suppresses both the population of these rare motifs and the long-range correlation of the dihedral angles. We argue that the long-range correlation of the polyglutamine homopeptide, along with the presence of these rare motifs, could be responsible for its aggregation phenomena

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device

BACKGROUND: There is a dearth of literature regarding management and outcomes of patients with a left ventricular assist device (LVAD) for advanced heart failure who develop intracranial hemorrhage (ICH). We conducted a case series from 2 centers highlighting patient outcomes and prognostic factors to help clinicians better understand and care for these high-risk patients. METHODS: A case series from 2 large-volume institutions (defined as large by the Nationwide Inpatient Sample hospital size, i.e., \u3e500 beds both with Departments of Neurosurgery and Advanced Heart Failure-Cardiology) was conducted to clarify the prognosis of patients with an LVAD and ICH. We included patients who were being treated with an LVAD who developed ICH. Patient-specific demographics and data regarding heart failure and intracranial hemorrhage characteristics were collected and analyzed to determine which factors contributed to overall survival. RESULTS: We analyzed 59 unique ICHs in patients being treated with an LVAD for heart failure. Initial Glasgow Coma Scale score, presence of midline shift, and ICH size were factors found to be predictive of mortality. One institution had a sicker patient population including patients with ICH with lower Glasgow Coma Scale score, presence of midline shift, and greater hemorrhage size, which led to overall higher mortality compared with the second institution. CONCLUSIONS: Patients being treated with an LVAD who develop ICH have poor outcomes. Predictive factors for same-admission mortality are lower initial Glasgow Coma Scale score, presence of midline shift, and greater ICH volume

Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device

BACKGROUND: There is a dearth of literature regarding management and outcomes of patients with a left ventricular assist device (LVAD) for advanced heart failure who develop intracranial hemorrhage (ICH). We conducted a case series from 2 centers highlighting patient outcomes and prognostic factors to help clinicians better understand and care for these high-risk patients. METHODS: A case series from 2 large-volume institutions (defined as large by the Nationwide Inpatient Sample hospital size, i.e., \u3e500 beds both with Departments of Neurosurgery and Advanced Heart Failure-Cardiology) was conducted to clarify the prognosis of patients with an LVAD and ICH. We included patients who were being treated with an LVAD who developed ICH. Patient-specific demographics and data regarding heart failure and intracranial hemorrhage characteristics were collected and analyzed to determine which factors contributed to overall survival. RESULTS: We analyzed 59 unique ICHs in patients being treated with an LVAD for heart failure. Initial Glasgow Coma Scale score, presence of midline shift, and ICH size were factors found to be predictive of mortality. One institution had a sicker patient population including patients with ICH with lower Glasgow Coma Scale score, presence of midline shift, and greater hemorrhage size, which led to overall higher mortality compared with the second institution. CONCLUSIONS: Patients being treated with an LVAD who develop ICH have poor outcomes. Predictive factors for same-admission mortality are lower initial Glasgow Coma Scale score, presence of midline shift, and greater ICH volume

Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device

BACKGROUND: There is a dearth of literature regarding management and outcomes of patients with a left ventricular assist device (LVAD) for advanced heart failure who develop intracranial hemorrhage (ICH). We conducted a case series from 2 centers highlighting patient outcomes and prognostic factors to help clinicians better understand and care for these high-risk patients. METHODS: A case series from 2 large-volume institutions (defined as large by the Nationwide Inpatient Sample hospital size, i.e., \u3e500 beds both with Departments of Neurosurgery and Advanced Heart Failure-Cardiology) was conducted to clarify the prognosis of patients with an LVAD and ICH. We included patients who were being treated with an LVAD who developed ICH. Patient-specific demographics and data regarding heart failure and intracranial hemorrhage characteristics were collected and analyzed to determine which factors contributed to overall survival. RESULTS: We analyzed 59 unique ICHs in patients being treated with an LVAD for heart failure. Initial Glasgow Coma Scale score, presence of midline shift, and ICH size were factors found to be predictive of mortality. One institution had a sicker patient population including patients with ICH with lower Glasgow Coma Scale score, presence of midline shift, and greater hemorrhage size, which led to overall higher mortality compared with the second institution. CONCLUSIONS: Patients being treated with an LVAD who develop ICH have poor outcomes. Predictive factors for same-admission mortality are lower initial Glasgow Coma Scale score, presence of midline shift, and greater ICH volume