Continued scaling of semiconductor devices has driven information technology into vastly diverse applications. The performance of ultrascaled transistors is strongly influenced by local electric ...field and strain. As the size of these devices approaches fundamental limits, it is imperative to develop characterization techniques with nanometer resolution and three-dimensional (3D) mapping capabilities for device optimization. Here, we report on the use of single erbium (Er) ions as atomic probes for the electric field and strain in a silicon ultrascaled transistor. Stark shifts on the Er3+ spectra induced by both the overall electric field and the local charge environment are observed. Changes in strain smaller than 3 × 10–6 are detected, which is around 2 orders of magnitude more sensitive than the standard techniques used in the semiconductor industry. These results open new possibilities for 3D mapping of the local strain and electric field in the channel of ultrascaled transistors.
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IJS, KILJ, NUK, PNG, UL, UM
High-throughput screening (HTS) of large compound collections typically results in numerous small molecule hits that must be carefully evaluated to identify valid drug leads. Although several ...filtering mechanisms and other tools exist that can assist the chemist in this process, it is often the case that costly synthetic resources are expended in pursuing false positives. We report here a rapid and reliable NMR-based method for identifying reactive false positives including those that oxidize or alkylate a protein target. Importantly, the reactive species need not be the parent compound, as both reactive impurities and breakdown products can be detected. The assay is called ALARM NMR (a La assay to detect reactive molecules by nuclear magnetic resonance) and is based on monitoring DTT-dependent 13C chemical shift changes of the human La antigen in the presence of a test compound or mixture. Extensive validation has been performed to demonstrate the reliability and utility of using ALARM NMR to assess thiol reactivity. This included comparing ALARM NMR to a glutathione-based fluorescence assay, as well as testing a collection of more than 3500 compounds containing HTS hits from 23 drug targets. The data show that current in silico filtering tools fail to identify more than half of the compounds that can act via reactive mechanisms. Significantly, we show how ALARM NMR data has been critical in identifying reactive compounds that would otherwise have been prioritized for lead optimization. In addition, a new filtering tool has been developed on the basis of the ALARM NMR data that can augment current in silico programs for identifying nuisance compounds and improving the process of hit triage.
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IJS, KILJ, NUK, PNG, UL, UM
The US Health and Human Services Pain Management Best Practices Inter-Agency Task Force initiated a public-private partnership which led to the publication of its report in 2019. The report ...emphasized the need for individualized, multimodal, and multidisciplinary approaches to pain management that decrease the over-reliance on opioids, increase access to care, and promote widespread education on pain and substance use disorders. The Task Force specifically called on specialty organizations to work together to develop evidence-based guidelines. In response to this report's recommendations, a consortium of 14 professional healthcare societies committed to a 2-year project to advance pain management for the surgical patient and improve opioid safety. The modified Delphi process included two rounds of electronic voting and culminated in a live virtual event in February 2021, during which seven common guiding principles were established for acute perioperative pain management. These principles should help to inform local action and future development of clinical practice recommendations.
Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of ...much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.
PURPOSELeft-digit bias is a phenomenon in which the leftmost digit of a number disproportionately influences decision making. We measured the effect of left-digit age bias on treatment ...recommendations for localized prostate cancer. MATERIALS AND METHODSWe included men with clinically localized prostate adenocarcinoma in Surveillance, Epidemiology, and End Results from 2004 to 2018 and the National Cancer Database from 2004 to 2016. Primary outcomes were recommendations for radiation therapy and radical prostatectomy. Regression discontinuity was used to assess whether age increase from 69 to 70 years was associated with disproportionate changes in treatment recommendations. RESULTSIn Surveillance, Epidemiology, and End Results, discontinuities were found in the proportion of patients recommended for radiation among the entire cohort (effect size 2.2%, P < .01) and among patients with Gleason 6 (1.6%, P < .01), Gleason 7 (2.5%, P < .01), and Gleason ≥8 (2.1%, P < .01) cancer, while the proportion recommended for prostatectomy decreased in the entire cohort (-1.4%, P < .01) and in patients with Gleason 7 cancer (-2.4%, P < .01). In the National Cancer Database, discontinuity from age 69 to 70 was found in recommendations for radiation in the entire cohort (effect size: 3.1%, P < .01) and in patients with Gleason 6 (2.2%, P < .01), Gleason 7 (4.0%, P < .01), and Gleason ≥8 (2.3%, P < .02) cancer, while the proportion recommended for prostatectomy decreased at this cutoff in the entire cohort (effect size: -2.7%, P < .01) and patients with Gleason 6 (-2.2%, P < .01) and Gleason 7 (-3.7%, P < .01) cancer. CONCLUSIONSIn patients with localized prostate cancer, left-digit age change from 69 to 70 was associated with disproportionately increased recommendations for radiation and decreased recommendations for prostatectomy.
Background:
Injury of the ulnar collateral ligament (UCL) has become increasingly common, particularly in overhead athletes. There is no consensus on management of the ulnar nerve in UCL ...reconstruction (UCLR) in patients with preoperative ulnar nerve symptoms, as literature supports both not decompressing the nerve as well as ulnar nerve transposition (UNT).
Hypothesis/Purpose:
The purpose of this study was to compare subjective clinical outcomes and return-to-sports (RTS) metrics between patients who received UNT during UCLR and a matched cohort who underwent UCLR alone. We hypothesized that there would be no significant difference in patient outcomes or RTS metrics between the cohorts.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
Using an institutional database, patients who underwent UCLR with UNT between 2007 and 2017 were retrospectively identified. These patients were matched based on sex, age at surgery (±3 years), and body mass index (±2 kg/m2) to a comparison group that underwent UCLR alone. Patients completed the Kerlan-Jobe Orthopaedic Clinic Shoulder & Elbow (KJOC) score, the Timmerman and Andrews elbow score, the Conway-Jobe scale, and custom patient satisfaction and RTS questionnaires.
Results:
Thirty patients who underwent UCLR with concomitant UNT and 30 matched patients who underwent UCLR without UNT were available for follow-up at a mean of 6.9 (3.4-9.9) and 8.1 (3.4-13.9) years, respectively. The UNT group reported similar KJOC (78.4 in UNT vs 76.8; P = .780), Conway-Jobe (60% excellent in UNT vs 77% excellent; P = .504), Timmerman and Andrews (86.2 in UNT vs 88.8; P = .496), and satisfaction scores (85.3% in UNT vs 89.3%; P = .512) compared with UCLR group. In terms of RTS rate (84% in UNT vs 93% in UCLR; P = .289) and duration required to RTS (11.1 months in UNT vs 12.5 months in UCLR; P = .176), the 2 groups did not significantly differ. Finally, despite significant differences in preoperative ulnar nerve symptoms (100% in UNT vs 7% in UCLR; P < .001), the 2 groups did not statistically differ in the proportion of patients who experienced postoperative ulnar nerve symptoms (13% in UNT vs 0% in UCLR; P = .112).
Conclusion:
This matched cohort analysis showed no statistically significant differences in patient-reported outcomes and RTS between patients undergoing UCLR with and without UNT.
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FSPLJ, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Introduction/Aim
Long‐term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP).
Methods
Patients with PPP in a double‐blind, ...placebo‐controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52‐week open‐label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity‐weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies.
Results
Sixty‐three adults (age, 19‐76 years) completed the double‐blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity‐weighted attack rates from baseline to week 61 (DCP/DCP n = 25, −1.00 P < .0001; placebo/DCP n = 20, −0.63 P = .01 and DCP/DCP, −2.25 P < .0001; placebo/DCP, −1.69 P = .01). Relatively smaller median decreases in weekly attack and severity‐weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; −0.14 P = .1 and −0.24 P = .09) than among those switching from placebo to DCP after 9 weeks (n = 16; −1.04 P = .049 and −2.72 P = .08). Common adverse events (AEs) were paresthesia and cognition‐related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution.
Discussion
One‐year open‐label DCP treatment after a 9‐week randomized, controlled study confirmed long‐term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition‐related AEs) were manageable in most patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental ...problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-γ and macrophage inflammatory protein-1β expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development-vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Burn injury is associated with endothelial dysfunction and coagulopathy and concomitant inhalation injury (IHI) increases morbidity and mortality. The aim of this work is to identify ...associations between IHI, coagulation homeostasis, vascular endothelium, and clinical outcomes in burn patients. One hundred and twelve patients presenting to a regional burn center were included in this retrospective cohort study. Whole blood was collected at set intervals from admission through 24 hours and underwent viscoelastic assay with rapid thromboelastography (rTEG). Syndecan-1 (SDC-1) on admission was quantified by ELISA. Patients were grouped by the presence (n = 28) or absence (n = 84) of concomitant IHI and rTEG parameters, fibrinolytic phenotypes, SDC-1, and clinical outcomes were compared. Of the 112 thermally injured patients, 28 (25%) had IHI. Most patients were male (68.8%) with a median age of 40 (interquartile range, 29–57) years. Patients with IHI had higher overall mortality (42.68% vs 8.3%; P < .0001). rTEG LY30 was lower in patients with IHI at hours 4 and 12 (P < .05). There was a pattern of increased abnormal fibrinolytic phenotypes among IHI patients. There was a greater proportion of IHI patients with endotheliopathy (SDC-1 > 34 ng/ml) (64.7% vs 26.4%; P = .008). There was a pattern of increased mortality among patients with IHI and endotheliopathy (0% vs 72.7%; P = .004). Significant differences between patients with and without IHI were found in measures assessing fibrinolytic potential and endotheliopathy. Mortality was associated with abnormal fibrinolysis, endotheliopathy, and IHI. However, the extent to which IHI-associated dysfunction is independent of TBSA burn size remains to be elucidated.
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