Use of a Novel Artificial Intelligence System Leads to the Detection of Significantly Higher Number of Adenomas During Screening and Surveillance Colonoscopy: Results From a Large, Prospective, US Multicenter, Randomized Clinical Trial.

INTRODUCTION: Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel artificial intelligence (AI) system, compared with standard high-definition colonoscopy, for APC measurement. METHODS: This was a US-based, multicenter, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE). Eligible average-risk subjects (45 years or older) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified intention-to-treat analysis was performed for all patients who completed colonoscopy with the primary outcome of APC. Secondary outcomes included positive predictive value (total number of adenomas divided by total polyps removed) and adenoma detection rate. RESULTS: In modified intention-to-treat analysis, of 1,031 subjects (age: 59.1 ± 9.8 years; 49.9% male), 510 underwent CAC vs 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared with CC: 0.99 ± 1.6 vs 0.85 ± 1.5, P = 0.02, incidence rate ratio 1.17 (1.03-1.33, P = 0.02) with no significant difference in the withdrawal time: 11.28 ± 4.59 minutes vs 10.8 ± 4.81 minutes; P = 0.11 between the 2 groups. Difference in positive predictive value of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI -9.56% to -1.48%. There were no significant differences in adenoma detection rate (46.9% vs 42.8%), advanced adenoma (6.5% vs 6.3%), sessile serrated lesion detection rate (12.9% vs 10.1%), and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared with CC: 1.68 ± 2.1 vs 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; P < 0.01). DISCUSSION: Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared with conventional high-definition colonoscopy without any increase in colonoscopy withdrawal time, thus supporting the use of AI-assisted colonoscopy to improve colonoscopy quality ( ClinicalTrials.gov NCT04979962).

Human proteins curing yeast prions.

Recognition that common human amyloidoses are prion diseases makes the use of the Saccharomyces cerevisiae prion model systems to screen for possible anti-prion components of increasing importance. [PSI+] and [URE3] are amyloid-based prions of Sup35p and Ure2p, respectively. Yeast has at least six anti-prion systems that together cure nearly all [PSI+] and [URE3] prions arising in their absence. We made a GAL-promoted bank of 14,913 human open reading frames in a yeast shuttle plasmid and isolated 20 genes whose expression cures [PSI+] or [URE3]. PRPF19 is an E3 ubiquitin ligase that cures [URE3] if its U-box is intact. DNAJA1 is a J protein that cures [PSI+] unless its interaction with Hsp70s is defective. Human Bag5 efficiently cures [URE3] and [PSI+]. Bag family proteins share a 110 to 130 residue "BAG domain"; Bag 1, 2, 3, 4, and 6 each have one BAG domain while Bag5 has five BAG domains. Two BAG domains are necessary for curing [PSI+], but one can suffice to cure [URE3]. Although most Bag proteins affect autophagy in mammalian cells, mutations blocking autophagy in yeast do not affect Bag5 curing of [PSI+] or [URE3]. Curing by Bag proteins depends on their interaction with Hsp70s, impairing their role, with Hsp104 and Sis1, in the amyloid filament cleavage necessary for prion propagation. Since Bag5 curing is reduced by overproduction of Sis1, we propose that Bag5 cures prions by blocking Sis1 access to Hsp70s in its role with Hsp104 in filament cleavage.

Study protocol for a randomized, controlled trial using a novel, family-centered diet treatment to prevent nonalcoholic fatty liver disease in Hispanic children.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading liver disorder among U.S. children and is most prevalent among Hispanic children with obesity. Previous research has shown that reducing the consumption of free sugars (added sugars + naturally occurring sugars in fruit juice) can reverse liver steatosis in adolescents with NAFLD. This study aims to determine if a low-free sugar diet (LFSD) can prevent liver fat accumulation and NAFLD in high-risk children. METHODS: In this randomized controlled trial, we will enroll 140 Hispanic children aged 6 to 9 years who are ≥50th percentile BMI and without a previous diagnosis of NAFLD. Participants will be randomly assigned to either an experimental (LFSD) or a control (usual diet + educational materials) group. The one-year intervention includes removal of foods high in free sugars from the home at baseline, provision of LFSD household groceries for the entire family (weeks 1-4, 12, 24, and 36), dietitian-guided family grocery shopping sessions (weeks 12, 24, and 36), and ongoing education and motivational interviewing to promote LFSD. Both groups complete assessment measures at baseline, 6, 12, 18, and 24 months. Primary study outcomes are percent hepatic fat at 12 months and incidence of clinically significant hepatic steatosis (>5%) + elevated liver enzymes at 24 months. Secondary outcomes include metabolic markers potentially mediating or moderating NAFLD pathogenesis. DISCUSSION: This protocol describes the rationale, eligibility criteria, recruitment strategies, analysis plan as well as a novel dietary intervention design. Study results will inform future dietary guidelines for pediatric NAFLD prevention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05292352.

Anti-Prion Systems Block Prion Transmission, Attenuate Prion Generation, Cure Most Prions as They Arise and Limit Prion-Induced Pathology in Saccharomyces cerevisiae.

All variants of the yeast prions [PSI+] and [URE3] are detrimental to their hosts, as shown by the dramatic slowing of growth (or even lethality) of a majority, by the rare occurrence in wild isolates of even the mildest variants and by the absence of reproducible benefits of these prions. To deal with the prion problem, the host has evolved an array of anti-prion systems, acting in normal cells (without overproduction or deficiency of any component) to block prion transmission from other cells, to lower the rates of spontaneous prion generation, to cure most prions as they arise and to limit the damage caused by those variants that manage to elude these (necessarily) imperfect defenses. Here we review the properties of prion protein sequence polymorphisms Btn2, Cur1, Hsp104, Upf1,2,3, ribosome-associated chaperones, inositol polyphosphates, Sis1 and Lug1, which are responsible for these anti-prion effects. We recently showed that the combined action of ribosome-associated chaperones, nonsense-mediated decay factors and the Hsp104 disaggregase lower the frequency of [PSI+] appearance as much as 5000-fold. Moreover, while Btn2 and Cur1 are anti-prion factors against [URE3] and an unrelated artificial prion, they promote [PSI+] prion generation and propagation.

Anti-Prion Systems in Saccharomyces cerevisiae Turn an Avalanche of Prions into a Flurry.

Prions are infectious proteins, mostly having a self-propagating amyloid (filamentous protein polymer) structure consisting of an abnormal form of a normally soluble protein. These prions arise spontaneously in the cell without known reason, and their effects were generally considered to be fatal based on prion diseases in humans or mammals. However, the wide array of prion studies in yeast including filamentous fungi revealed that their effects can range widely, from lethal to very mild (even cryptic) or functional, depending on the nature of the prion protein and the specific prion variant (or strain) made by the same prion protein but with a different conformation. This prion biology is affected by an array of molecular chaperone systems, such as Hsp40, Hsp70, Hsp104, and combinations of them. In parallel with the systems required for prion propagation, yeast has multiple anti-prion systems, constantly working in the normal cell without overproduction of or a deficiency in any protein, which have negative effects on prions by blocking their formation, curing many prions after they arise, preventing prion infections, and reducing the cytotoxicity produced by prions. From the protectors of nascent polypeptides (Ssb1/2p, Zuo1p, and Ssz1p) to the protein sequesterase (Btn2p), the disaggregator (Hsp104), and the mysterious Cur1p, normal levels of each can cure the prion variants arising in its absence. The controllers of mRNA quality, nonsense-mediated mRNA decay proteins (Upf1, 2, 3), can cure newly formed prion variants by association with a prion-forming protein. The regulator of the inositol pyrophosphate metabolic pathway (Siw14p) cures certain prion variants by lowering the levels of certain organic compounds. Some of these proteins have other cellular functions (e.g., Btn2), while others produce an anti-prion effect through their primary role in the normal cell (e.g., ribosomal chaperones). Thus, these anti-prion actions are the innate defense strategy against prions. Here, we outline the anti-prion systems in yeast that produce innate immunity to prions by a multi-layered operation targeting each step of prion development.

Antiprion systems in yeast cooperate to cure or prevent the generation of nearly all [PSI+] and [URE3] prions.

[PSI+] and [URE3] are prions of Saccharomyces cerevisiae based on amyloids of Sup35p and Ure2p, respectively. In normal cells, antiprion systems block prion formation, cure many prions that arise, prevent infection by prions, and prevent toxicity of those prions that escape the other systems. The upf1Δ, ssz1Δ, and hsp104T160M single mutants each develop [PSI+] at 10- to 15-fold, but the triple mutant spontaneously generates [PSI+] at up to ∼5,000-fold the wild-type rate. Most such [PSI+] variants are cured by restoration of any one of the three defective antiprion systems, defining a previously unknown type of [PSI+] variant and proving that these three antiprion systems act independently. Generation of [PSI+] variants stable in wild-type cells is also increased in upf1Δ ssz1Δ hsp104T160M strains 25- to 500-fold. Btn2 and Cur1 each cure 90% of [URE3] prions generated in their absence, but we find that btn2Δ or cur1Δ diminishes the frequency of [PSI+] generation in an otherwise wild-type strain. Most [PSI+] isolates in a wild-type strain are destabilized on transfer to a btn2Δ or cur1Δ host. Single upf1Δ or hsp104T160M mutants show the effects of btn2Δ or cur1Δ but not upf1Δ ssz1Δ hsp104T160M or ssz1Δ hsp104T160M strains. The disparate action of Btn2 on [URE3] and [PSI+] may be a result of [PSI+]'s generally higher seed number and lower amyloid structural stability compared with [URE3]. Thus, prion generation is not a rare event, but the escape of a nascent prion from the surveillance by the antiprion systems is indeed rare.

Innate immunity to prions: anti-prion systems turn a tsunami of prions into a slow drip.

The yeast prions (infectious proteins) [URE3] and [PSI+] are essentially non-functional (or even toxic) amyloid forms of Ure2p and Sup35p, whose normal function is in nitrogen catabolite repression and translation termination, respectively. Yeast has an array of systems working in normal cells that largely block infection with prions, block most prion formation, cure most nascent prions and mitigate the toxic effects of those prions that escape the first three types of systems. Here we review recent progress in defining these anti-prion systems, how they work and how they are regulated. Polymorphisms of the prion domains partially block infection with prions. Ribosome-associated chaperones ensure proper folding of nascent proteins, thus reducing [PSI+] prion formation and curing many [PSI+] variants that do form. Btn2p is a sequestering protein which gathers [URE3] amyloid filaments to one place in the cells so that the prion is often lost by progeny cells. Proteasome impairment produces massive overexpression of Btn2p and paralog Cur1p, resulting in [URE3] curing. Inversely, increased proteasome activity, by derepression of proteasome component gene transcription or by 60S ribosomal subunit gene mutation, prevents prion curing by Btn2p or Cur1p. The nonsense-mediated decay proteins (Upf1,2,3) cure many nascent [PSI+] variants by associating with Sup35p directly. Normal levels of the disaggregating chaperone Hsp104 can also cure many [PSI+] prion variants. By keeping the cellular levels of certain inositol polyphosphates / pyrophosphates low, Siw14p cures certain [PSI+] variants. It is hoped that exploration of the yeast innate immunity to prions will lead to discovery of similar systems in humans.

Innate immunity to yeast prions: Btn2p and Cur1p curing of the [URE3] prion is prevented by 60S ribosomal protein deficiency or ubiquitin/proteasome system overactivity.

[URE3] is an amyloid-based prion of Ure2p, a negative regulator of poor nitrogen source catabolism in Saccharomyces cerevisiae. Overproduced Btn2p or its paralog Cur1p, in processes requiring Hsp42, cure the [URE3] prion. Btn2p cures by collecting Ure2p amyloid filaments at one place in the cell. We find that rpl4aΔ, rpl21aΔ, rpl21bΔ, rpl11bΔ, and rpl16bΔ (large ribosomal subunit proteins) or ubr2Δ (ubiquitin ligase targeting Rpn4p, an activator of proteasome genes) reduce curing by overproduced Btn2p or Cur1p. Impaired curing in ubr2Δ or rpl21bΔ is restored by an rpn4Δ mutation. No effect of rps14aΔ or rps30bΔ on curing was observed, indicating that 60S subunit deficiency specifically impairs curing. Levels of Hsp42p, Sis1p, or Btn3p are unchanged in rpl4aΔ, rpl21bΔ, or ubr2Δ mutants. Overproduction of Cur1p or Btn2p was enhanced in rpn4Δ and hsp42Δ mutants, lower in ubr2Δ strains, and restored to above wild-type levels in rpn4Δ ubr2Δ strains. As in the wild-type, Ure2N-GFP colocalizes with Btn2-RFP in rpl4aΔ, rpl21bΔ, or ubr2Δ strains, but not in hsp42Δ. Btn2p/Cur1p overproduction cures [URE3] variants with low seed number, but seed number is not increased in rpl4aΔ, rpl21bΔ or ubr2Δ mutants. Knockouts of genes required for the protein sorting function of Btn2p did not affect curing of [URE3], nor did inactivation of the Hsp104 prion-curing activity. Overactivity of the ubiquitin/proteasome system, resulting from 60S subunit deficiency or ubr2Δ, may impair Cur1p and Btn2p curing of [URE3] by degrading Cur1p, Btn2p or another component of these curing systems.

Proteasome Control of [URE3] Prion Propagation by Degradation of Anti-Prion Proteins Cur1 and Btn2 in Saccharomyces cerevisiae.

[URE3] is a prion of the nitrogen catabolism controller, Ure2p, and [PSI+] is a prion of the translation termination factor Sup35p in S. cerevisiae. Btn2p cures [URE3] by sequestration of Ure2p amyloid filaments. Cur1p, paralogous to Btn2p, also cures [URE3], but by a different (unknown) mechanism. We find that an array of mutations impairing proteasome assembly or MG132 inhibition of proteasome activity result in loss of [URE3]. In proportion to their prion-curing effects, each mutation affecting proteasomes elevates the cellular concentration of the anti-prion proteins Btn2 and Cur1. Of >4,600 proteins detected by SILAC, Btn2p was easily the most overexpressed in a pre9Δ (α3 core subunit) strain. Indeed, deletion of BTN2 and CUR1 prevents the prion-curing effects of proteasome impairment. Surprisingly, the 15 most unstable yeast proteins are not increased in pre9Δ cells suggesting altered proteasome specificity rather than simple inactivation. Hsp42, a chaperone that cooperates with Btn2 and Cur1 in curing [URE3], is also necessary for the curing produced by proteasome defects, although Hsp42p levels are not substantially altered by a proteasome defect. We find that pre9Δ and proteasome chaperone mutants that most efficiently lose [URE3], do not destabilize [PSI+] or alter cellular levels of Sup35p. A tof2 mutation or deletion likewise destabilizes [URE3], and elevates Btn2p, suggesting that Tof2p deficiency inactivates proteasomes. We suggest that when proteasomes are saturated with denatured/misfolded proteins, their reduced degradation of Btn2p and Cur1p automatically upregulates these aggregate-handling systems to assist in the clean-up.

Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants.

The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor, Sup35p. For known pathogenic prions, such as [PSI+], a single protein can form an array of different amyloid structures (prion variants) each stably inherited and with differing biological properties. The ribosome-associated chaperones, Ssb1/2p (Hsp70s), and RAC (Zuo1p (Hsp40) and Ssz1p (Hsp70)), enhance de novo protein folding by protecting nascent polypeptide chains from misfolding and maintain translational fidelity by involvement in translation termination. Ssb1/2p and RAC chaperones were previously found to inhibit [PSI+] prion generation. We find that most [PSI+] variants arising in the absence of each chaperone were cured by restoring normal levels of that protein. [PSI+] variants hypersensitive to Ssb1/2p have distinguishable biological properties from those hypersensitive to Zuo1p or Ssz1p. The elevated [PSI+] generation frequency in each deletion strain is not due to an altered [PIN+], another prion that primes [PSI+] generation. [PSI+] prion generation/propagation may be inhibited by Ssb1/2/RAC chaperones by ensuring proper folding of nascent Sup35p, thus preventing its joining amyloid fibers. Alternatively, the effect of RAC/Ssb mutations on translation termination and the absence of an effect on the [URE3] prion suggest an effect on the mature Sup35p such that it does not readily join amyloid filaments. Ssz1p is degraded in zuo1Δ [psi-] cells, but not if the cells carry any of several [PSI+] variants. Our results imply that prions arise more frequently than had been thought but the cell has evolved exquisite antiprion systems that rapidly eliminate most variants.

Dual-histamine receptor blockade with cetirizine - famotidine reduces pulmonary symptoms in COVID-19 patients.

BACKGROUND: The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 receptor blockers improve COVID-19 inpatient outcomes? METHODS: A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg b.i.d. and famotidine 20 mg b.i.d. plus standard-of-care. RESULTS: Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine receptor blockade for at least 48 h, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 h of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited beneficial reductions in inpatient mortality and symptom progression when compared to published reports of COVID-19 inpatients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. CONCLUSIONS: This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine receptor blockers.

How Do Yeast Cells Contend with Prions?

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear ß-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.

Dual-Histamine Blockade with Cetirizine - Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients

BackgroundThe COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 receptor blockers improve COVID-19 inpatient outcomes? MethodsA physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg b.i.d. and famotidine 20 mg b.i.d. plus standard-of-care. ResultsOf all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine receptor blockade for at least 48 hours, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 hours of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited beneficial reductions in inpatient mortality and symptom progression when compared to published reports of COVID-19 inpatients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. ConclusionsThis physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine receptor blockers.

Breast-Specific Sensuality and Appearance Satisfaction: Comparison of Breast-Conserving Surgery and Nipple-Sparing Mastectomy.

BACKGROUND: We demonstrated previously that lumpectomy (L) patients reported higher appearance satisfaction, appreciation of a pleasurable breast caress, and persistence of the breast during intimacy than mastectomy with reconstruction, which we used to describe breast-specific sensuality. Our current objective was to compare breast-specific sensuality between L and nipple-sparing mastectomy (NSM). DESIGN: An anonymous, cross-sectional survey was distributed to breast cancer survivors between 2014 and 2016. Eligible patients underwent operation between 2000 and 2014, were adults older than 18 years, English-speaking, and at least one year into the post-operative period. Demographic characteristics, treatment details, Female Sexual Function Index metrics, and investigator-generated questions about appearance satisfaction and breast-specific sensuality were collected. RESULTS: Of the 600 women who participated, 585 surveys were eligible. Surgical modality was reported as L by 406 (69.4%), mastectomy alone by 50 (8.5%), and mastectomy with reconstruction by 129 (22.1%). Nipple-preservation data were available for 47 of 129 mastectomy with reconstruction patients (36.4%), with 21 NSM and 26 non-nipple-sparing mastectomy patients. Favorable postoperative appearance satisfaction was reported by 76.2% of L and 71.4% of NSM (p = 0.039). Lumpectomy patients reported feeling more comfortable being seen undressed than NSM patients (82.4% vs 71.4%; p = 0.0003). The chest remained a part of intimacy for 65.4% of L patients vs 42.9% of NSM patients (p = 0.0009). A pleasurable breast caress was reported more frequently by L patients than NSM patients (66.2% vs 20%; p ≤ 0.0001). The breast caress was unpleasant for 40% of NSM patients, nearly 4-fold higher than L patients (11.3%; p < 0.0001). CONCLUSIONS: NSM patients were significantly less satisfied with appearance, less comfortable being seen undressed, had decreased persistence of breast intimacy, and experienced a less pleasurable breast caress than L patients. Counseling patients about these findings will empower informed decision making, optimize expectations, and can enhance postoperative satisfaction.

Scholarly Output by Army General Surgery Residents.

INTRODUCTION: To characterize and compare the scholarly activity of applicants to Army First Year Graduate Medical Education (FYGME) general surgery positions over the course of a residency. METHODS: All applicants for the 2011-2012 Army FYGME positions in general surgery were included. Applications were used to obtain demographics and peer-reviewed publications. Publications were verified using PubMed and Google Scholar. Applicants were tracked for acceptance to a FYGME position, graduation from a general surgery program, and future publications. Comparisons were made between selectees and non-selectees. RESULTS: There were 46 applicants for 22 positions. Seven of the selectees (32%) had prior publications versus three non-selectees (12%; p < 0.109). Eighteen of the selectees went on to complete a general surgery residency by 2017. Of those who completed a general surgery residency, 16 (89%) have at least one publication with the mean number of publications of 4.0 versus 10 (43%), and of those not selected had at least one publication and the mean number of publications was 0.7 (p < 0.05). CONCLUSIONS: The majority of applications for general surgery residencies have no prior research publications. However, after 6 years, graduates of a general surgery residency have significantly published out those not selected for training.

Current status of opioid addiction treatment and related preclinical research.

Opioid use disorders (OUDs) are diseases of the brain with behavioral, psychological, neurobiological, and medical manifestations. Vulnerability to OUDs can be affected by factors such as genetic background, environment, stress, and prolonged exposure to µ-opioid agonists for analgesia. Two standard-of-care maintenance medications, methadone and buprenorphine-naloxone, have a long-term positive influence on health of persons with opioid addiction. Buprenorphine and another medication, naltrexone, have also been approved for administration as monthly depot injections. However, neither medication is used as widely as needed, due largely to stigma, insufficient medical education or training, inadequate resources, and inadequate access to treatment. Ongoing directions in the field include (i) personalized approaches leveraging genetic factors for prediction of OUD vulnerability and prognosis, or for targeted pharmacotherapy, and (ii) development of novel analgesic medicines with new neurobiological targets with reduced abuse potential, reduced toxicity, and improved effectiveness, especially for chronic pain states other than cancer pain.

Electrostatic subframing and compressive-sensing video in transmission electron microscopy.

We present kilohertz-scale video capture rates in a transmission electron microscope, using a camera normally limited to hertz-scale acquisition. An electrostatic deflector rasters a discrete array of images over a large camera, decoupling the acquisition time per subframe from the camera readout time. Total-variation regularization allows features in overlapping subframes to be correctly placed in each frame. Moreover, the system can be operated in a compressive-sensing video mode, whereby the deflections are performed in a known pseudorandom sequence. Compressive sensing in effect performs data compression before the readout, such that the video resulting from the reconstruction can have substantially more total pixels than that were read from the camera. This allows, for example, 100 frames of video to be encoded and reconstructed using only 15 captured subframes in a single camera exposure. We demonstrate experimental tests including laser-driven melting/dewetting, sintering, and grain coarsening of nanostructured gold, with reconstructed video rates up to 10 kHz. The results exemplify the power of the technique by showing that it can be used to study the fundamentally different temporal behavior for the three different physical processes. Both sintering and coarsening exhibited self-limiting behavior, whereby the process essentially stopped even while the heating laser continued to strike the material. We attribute this to changes in laser absorption and to processes inherent to thin-film coarsening. In contrast, the dewetting proceeded at a relatively uniform rate after an initial incubation time consistent with the establishment of a steady-state temperature profile.