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Approximately 3 million U.S. children are considered to have medical complexity, a subset of children that are the most medically fragile and have the most intensive health care needs of all children with special health care needs. Families with children with medical complexity often experience myriad physical, mental, and financial stressors impacting their well-being, family functioning, and mental health. Background information and clinical implications for counselors working with this population will be discussed.

There is concern regarding the competency of today's general surgery graduates as a large proportion defer independent practice in favor of additional fellowship training. Little is known about the graduates who directly enter general surgery practice and if their operative experiences during residency differ from graduates who pursue fellowship.Nineteen Accreditation Council for Graduate Medical Education-accredited general surgery programs from the US Resident OPerative Experience Consortium were included. Demographics, career choice, and case logs from graduates between 2010 to 2020 were analyzed.There were 1,264 general surgery residents who graduated over the 11-year period. A total of 248 (19.6%) went directly into practice and 1,016 (80.4%) pursued fellowship. Graduates directly entering practice were more likely to be a high-volume resident (43.1% vs 30.5%, P.01) and graduate from a high-volume program (49.2% vs 33.0%, P.01). Direct-to-practice graduates performed 53 more cases compared with fellowship-bound graduates (1,203 vs 1,150, P.01). On multivariable analysis, entering directly into practice was positively associated with total surgeon chief case volume (odds ratio = 1.47, 95% confidence interval 1.18-1.84, P.01) and graduating from a US medical school (odds ratio = 2.54, 95% confidence interval 1.45-4.44, P.01) while negatively associated with completing a dedicated research experience (odds ratio = 0.31, 95% confidence interval 0.22-0.45, P.01).This is the first multi-institutional study exploring resident operative experience and career choice. These data suggest residents who desire immediate practice can tailor their experience with less research time and increased operative volume. These data may be helpful for programs when designing their experience for residents with different career goals.

Under the revised lead and copper rule, schools and daycare centers will need to conduct lead and copper sampling. The California Division of Drinking Water required Public Water Systems to assist local schools in testing water for lead between 2017 and 2020. There were 43,803 samples collected from 7,058 schools in 864 school districts. In total, 5.2% of the samples had lead present in concentrations greater than the Detection Limit for Reporting (DLR) of 5 μg/L, and 1.1% of samples had lead concentrations greater than the Action Level (AL) of 15 μg/L. When broken down by counties, these patterns are consistent throughout most of the State. Drinking fountains had significantly lower frequencies of results above the DLR and AL than samples collected from sinks and food preparation areas. Chloride, bicarbonate, and pH appeared to influence the frequency of results above the DLR and AL.

Under new regulations In the USA, all Community Water Systems (CWS) need to develop an inventory of their lead service lines (LSL) and determine those owned by their customers. This study will present an approach to address this issue that meets both the letter and the spirit of the law but is also practical and affordable. The first part examines the results of a survey of service lines conducted in California. Eleven million CWS-owned service lines were inventoried, but only four were LSL. The second part of the study was to examine the how California effectively outlawed LSL through the use of plumbing codes. The third part of the study was to determine if these codes had been as effectively implemented on the customer's service lines by examining the customer's service lines in Pasadena. No LSL were found.

This article introduces a simple application of contest theory that neatly captures how Boulding’s ‘loss of strength gradient’ determines the geographic extent of territory. We focus on the ‘supply side’ of territorial conflict, showing how the costs of initiating and escalating conflict over spatially dispersed resources shape the nature and scope of territory. We show that economies of scale in the production of violence and varying costs of projecting power at a distance combine to affect the intensive and extensive margins of conflict, and ultimately the geographic distribution of territory. Comparative statics analysis shows how the distribution of conflict and territory change as costs change, helping shed light on, for example, why new transportation technologies have historically led to a redrawing of territorial boundaries. We test and probe the boundaries of this model in two experiments varying the marginal costs of conflict over space and the fixed costs of entry. Increases in both costs interact to increase the probability of exclusive territories. The first experiment directly tests the theory in a static, one-shot setting that strictly matches the information conditions studied in the theory. The second experiment examines conflict behavior under conditions analogous to those in conflicts outside the lab: where no contestant knows the probability of winning, let alone the function determining that probability, and parties interact repeatedly. Median behavior closely tracks equilibrium predictions in all treatments.

This paper concerns the business of law, a subject ignored by legal academia and sugarcoated by the organized bar. If law professors express little or no interest in this subject, their students most certainly do. Indeed, I have found that students are desperately hungry for information on the day-to-day realities of working in a law firm. Students are especially keen to learn about possible paths for career advancement within firms, across them, or across the organizations served by the firms. Paths for career advancement do exist, but they are not easy to find or pursue. Law firms are hardly going to assist their younger lawyers in this endeavor, as the interests of senior lawyers do not align with the interests of the associates. In fact, senior lawyers are engaged in competition with each other. As a result, younger lawyers may experience significant uncertainty and frustration in determining how to promote their careers. This paper is my attempt to shed light on the hidden law firm dynamics likely to shape the career success or failure of junior lawyers working in law firms. Such knowledge may empower associates to think strategically about their careers, as their senior colleagues already do. The ideas presented here are based on my fourteen years of teaching in a law school and my eleven years working as an associate attorney or foreign legal consultant at four law firms in three countries.

Peer feedback, or feedback given by a learner to another learner, is an important active learning strategy. Hierarchy and stereotypes may affect interprofessional (IP) learner-to-learner feedback. The aim was to assess the efficacy of an educational module for IP learners in delivering effective feedback during trauma simulations.Multiple simulation events designed to improve teamwork and leadership skills during trauma simulations included IP learners (residents and nurses). Participants completed a pre-course educational module on IP peer feedback. The Trauma Team Competence Assessment-24 tool structured feedback. Learners completed pre/post-assessments utilizing IP Collaborative Competencies Attainment Survey (ICCAS).Twenty-five learners participated in the trauma simulations (13 general surgery and 5 emergency residents, 3 medical students, 4 nurses). The majority of learners had either not received any previous training in how to effectively deliver peer feedback (40%) or had engaged in self-directed learning only (24%). Most learners (64%) had delivered peer feedback less than ten times. Learner knowledge and confidence in delivering feedback to fellow IP learners improved after simulations. All learners felt the feedback received was useful to their daily practice (68% agree, 32% strongly agree). All participants agreed that the simulation achieved each of the ICCAS competencies.Formal education on IP peer feedback is rare. This pilot work demonstrates educational modules with a foundation in validated tools can be effective in improving learner knowledge and confidence in the process. Engaging in IP peer feedback may also serve to flatten hierarchies that can challenge effective interprofessional teamwork.

PDF - 828K, Interrogation of an HNC Affymetrix U-133a microarray database for s50-TBG-RNAi-CK2-related proteins in human HNC tumor vs. normal oral mucosa.

PDF - 53K, Legends for Supplemental Figures 1 and 2.

PDF - 1588K, Weight change in mice for SCC-15, UM-11b and FaDu xenograft flank tumor models of HNSCC following treatment with s50-TBG-RNAi-CK2.

PDF - 53K, Hematological profile in FaDu metastatic spleen study mice 3 days post-treatment.

PDF - 48K, Serum chemistry in FaDu metastatic spleen study mice 3 days post-treatment.

PDF - 46K, Origin and characteristics of tumor cell lines used in HNSCC survival studies.

Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub–50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell–specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα′ mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise. Mol Cancer Ther; 13(8); 2018–29. ©2014 AACR.

Supplemental Figure S4: (A) S2013 mouse demonstrate localization of V7-750 probe, but not K7-750 to the region of the tumor bed, signal intensity in the pancreas tumor of S2013 mice with injection of V7-750 is 578.3 MSOT a.u., compared to 5.1 for K7-750 with p=0.0005. K7-750 signal was largely localized in the kidney.(B) Orthogonal views of the pancreatic tumor bed at 4 hours demonstrate distribution of V7-750 probe signal throughout the tumor bed at 4 hours, while minimal accumulation is observed with K7-750.

Supplemental Figure Legend from Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo

Supplemental Figure S3: Elliptical 3.5 mm2 ROIs were drawn based upon anatomical location and this size was maintained for relative quantitation of signal accumulation in the pancreas tumor, kidney, and liver. Because the liver and kidney are more easily identified in separate slices, two slices are shown which also contain the pancreas tumor. The location of orthotopic tumors was identified based upon the presence of deoxy-hemoglobin and relative location of the spleen and kidney as indicated by a yellow ellipse (A-B). Due to the location of the pancreas tumor and to prevent errors in organ identification, elliptical 3.5 mm2 ROIs were also drawn in the (A) uninvolved liver (red ellipse) and (B) opposite kidney (white ellipse). The 3.5 mm2 ellipse size was maintained among all ROIs in all mice and for all organs, but ROIs were rotated as needed based upon deoxy-hemoglobin localization to ensure that the probe accumulation within the pancreas tumors as accurate.

Supplemental Figure S1: (A) Uv-Vis absorbance of K7-750 and V7-750 probes at 40 μM peptide concentration. Absorbance peak at 280 nm shows the peptide peak, while absorbance peak at 750 nm shows the dye peak. (B) Normalized absorbance of V7-750, K7-750, deoxy-hemoglobin, and oxy-hemoglobin. These spectra were utilized for spectral unmixing of images acquired using MSOT imaging.

Chronic nicotine results in dependence with withdrawal symptoms upon discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity, however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene FOS during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity they were organized into two anticorrelated networks that were separated into basal forebrain projecting and brainstem-thalamic projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression ofChrna2,Chrna3,Chrna10, andChrndmRNA of each brain region correlated with withdrawal-induced changes in FOS expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced FOS expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.Significance StatementDiscontinuation of nicotine use in dependent users is associated with increased whole-brain activation and functional connectivity and leads to withdrawal symptoms. Here we investigated the contribution of the nicotinic cholinergic receptors and main cholinergic projecting brain areas in the whole-brain changes associated with withdrawal. This not only allowed us to visualize and confirm the previously described duality of the cholinergic brain system using this novel methodology, but also identify nicotinic receptors together with 1751 other genes that contribute, and could thus be targets for treatments against, nicotine withdrawal and dependence.

Supplemental Figure S5 The movie clip demonstrates spectrally unmixed oxy-hemoglobin (red color, left panel), deoxy-hemoglobin (blue color, middle panel), and V7-750 probe (green color, right panel) which were obtained using MSOT imaging as in Figure 3. Of special note, deoxy-hemoglobin (middle panel) denotes tumor location and corresponds to V7-750 signal (right panel).

Background: pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer.Methods: A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model.Results: In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7-750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7-750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging.Conclusions: Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer. Clin Cancer Res; 21(20); 4576–85. ©2015 AACR.See related commentary by Reshetnyak, p. 4502

Supplemental Figure S6: Dosimetry analysis demonstrates accumulation of V7-750 and K7-750 ex vivo in the liver, kidney, and pancreas tumor from planar fluorescent images.

Supplemental Figure S2: As the K7-750 probe did not bind to pancreas tumors, deoxy-hemoglobin signal was utilized to denote the location of the pancreas tumors. Orthogonal views of deoxy-hemoglobin signal indicate the location of the pancreatic tumor bed in both S2VP10 and S2013 xenografts. (A) Orthogonal view of deoxy-hemoglobin signal indicating the S2VP10 tumor within the mouse. Mouse shown is the same mouse shown as injected with V7-750 probe in Figure 3. MSOT images of this mouse are also available as a movie clip (Supplement Figure S5). (B) Orthogonal view of deoxy-hemoglobin signal indicating the S2VP10 tumor within the mouse that was injected with K7-750 (mouse shown from Figure 3).

BackgroundAztreonam/avibactam is under development to treat infections caused by Gram-negative bacteria. We evaluated the in vitro activities of aztreonam/avibactam and comparators against a global collection of carbapenem-resistant Enterobacterales (CRE), including ceftazidime/avibactam-resistant isolates.MethodsIsolates were consecutively collected (24 924; 1/patient) from 69 medical centres in 36 countries during 2019–21. Isolates were susceptibility tested by CLSI broth microdilution. All CRE isolates (n = 1098; 4.4%) were in silico screened for carbapenemase (CPE) genes after genome sequencing. CRE susceptibility results were stratified by CPE, geography and resistance phenotype.ResultsAztreonam/avibactam inhibited 99.6% of CREs at ≤8 mg/L (MIC50/90, 0.25/0.5 mg/L), including 98.9% (345/349) of ceftazidime/avibactam-resistant isolates. Aztreonam/avibactam activity was consistent across geographical regions (98.9%–100.0% inhibited at ≤8 mg/L), but susceptibility to comparators varied markedly. Susceptibility (CLSI criteria) for ceftazidime/avibactam and meropenem/vaborbactam ranged from 80.2% and 77.5% in Western Europe to 39.5% and 40.3% in the Asia-Pacific region, respectively. Aztreonam/avibactam retained activity against isolates non-susceptible to colistin (99.7% inhibited at ≤8 mg/L) or tigecycline (98.6% inhibited at ≤8 mg/L). A CPE gene was identified in 972 CRE isolates (88.5%). The most common CPEs were KPC (43.1% of CREs), NDM (26.6%) and OXA-48–like (18.7%); 57 isolates (5.2%) had >1 CPE gene. Aztreonam/avibactam inhibited 99.9% of CPE producers at ≤8 mg/L, whereas ceftazidime/avibactam and meropenem/vaborbactam exhibited limited activity against isolates producing MBL and/or OXA-48-like enzymes.ConclusionsAztreonam/avibactam activity was not adversely affected by clinically relevant CPEs. Our results support aztreonam/avibactam development to treat infections caused by CRE, including MBL producers.

Perineuronal nets (PNNs) are dense, negatively charged extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. Synapses can be embedded and stabilized by PNNs believed to prevent synaptic plasticity. We find that in cortical fast-spiking interneurons synaptic terminals localize to perforations in the PNNs, 95% of which contain either excitatory or inhibitory synapses or both. The majority of terminals also colocalize with astrocytic processes expressing Kir4.1 as well as glutamate (Glu) and GABA transporters, hence can be considered tripartite synapses. In the adult brain, degradation of PNNs does not alter axonal terminals but causes expansion of astrocytic coverage of the neuronal somata. However, loss of PNNs impairs astrocytic transmitter and K+ uptake and causes spillage of synaptic Glu into the extrasynaptic space. This data suggests a hitherto unrecognized role of PNNs, to synergize with astrocytes to contain synaptically released signals.

BackgroundThe Clinical and Laboratory Standards Institute (CLSI) lowered the Enterobacterales-susceptible/-resistant breakpoints for amikacin in 2023 from ≤16/≥64 mg/L to ≤4/≥16 mg/L and the breakpoints for gentamicin and tobramycin from ≤4/≥16 mg/L to ≤2/≥8 mg/L. Because aminoglycosides are frequently used to treat infections caused by multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE), we evaluated the impact of these changes on the susceptibility rates (%S) of Enterobacterales collected from US medical centers.MethodsA total of 9809 Enterobacterales isolates were consecutively collected (1/patient) from 37 US medical centers in 2017–2021 and susceptibility was tested by broth microdilution. Susceptibility rates were calculated using CLSI 2022, CLSI 2023, and US Food and Drug Administration 2022 criteria. Aminoglycoside-nonsusceptible isolates were screened for genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases (16RMT).ResultsThe CLSI breakpoint changes mostly affected amikacin, especially against MDR (94.0%S to 71.0%S), extended-spectrum β-lactamase (ESBL)-producing (96.9%S to 79.7%S), and CRE (75.2%S to 59.0%S) isolates. Plazomicin was active against 96.4% of isolates and retained potent activity against CRE (94.0%S), ESBL-producing (98.9%S), and MDR (94.8%S) isolates. Gentamicin and tobramycin showed limited activity against resistant subsets of Enterobacterales. The AME-encoding genes and 16RMT were observed in 801 (8.2%) and 11 (0.1%) isolates, respectively. Plazomicin was active against 97.3% of the AME producers.ConclusionsThe spectrum of activity of amikacin against resistant subsets of Enterobacterales was drastically reduced when interpretative criteria based on pharmacokinetic/pharmacodynamic parameters that are currently used to establish breakpoints for other antimicrobials were applied. Plazomicin was markedly more active than amikacin, gentamicin, or tobramycin against antimicrobial-resistant Enterobacterales.

Objective To report the 30-day outcomes of patients with perioperative SARS-CoV-2 infection undergoing surgery in the USA. Summary background data Uncertainty regarding the postoperative risks of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Methods As part of the COVIDSurg multicenter study, all patients aged ≥17 years undergoing surgery between January 1 and June 30, 2020 with perioperative SARS-CoV-2 infection in 70 hospitals across 27 states were included. The primary outcomes were 30-day mortality and pulmonary complications. Multivariable analyses (adjusting for demographics, comorbidities, and procedure characteristics) were performed to identify predictors of mortality. Results A total of 1,581 patients were included; more than half of them were males (n= 822, 52.0%) and older than 50 years (n=835, 52.8%). Most procedures (n=1,261, 79.8%) were emergent, and laparotomies (n= 538, 34.1%). The mortality and pulmonary complication rates were 11.0 and 39.5%, respectively. Independent predictors of mortality included age ≥70 years (OR 2.46, 95% CI [1.65-3.69]), male sex (2.26 [1.53-3.35]), ASA grades 3-5 (3.08 [1.60-5.95]), emergent surgery (2.44 [1.31-4.54]), malignancy (2.97 [1.58-5.57]), respiratory comorbidities (2.08 [1.30-3.32]), and higher Revised Cardiac Risk Index (1.20 [1.02-1.41]). While statewide elective cancelation orders were not associated with a lower mortality, a sub-analysis showed it to be associated with lower mortality in those who underwent elective surgery (0.14 [0.03-0.61]). Conclusions Patients with perioperative SARS-CoV-2 infection have a significantly high risk for postoperative complications, especially elderly males. Postponing elective surgery and adopting non-operative management, when reasonable, should be considered in the USA during the pandemic peaks.

Objective This study investigated vocalization and language environment longitudinally in infants with cleft palate (CP) based on day-long audio recordings collected in their natural environments. Design Language Environment Analysis (LENA) data from all-day recordings at home were collected at 3-month intervals for infants from 4-6 to 16-18 months of age. The recordings were analyzed using experimentally blinded human coding as well as LENA automated analysis. Participants Ten infants with CP (± cleft lip) and 10 age-matched infants without CP. Main Outcome Measures Several measurements were obtained from the LENA automated analysis software. In addition, human coded measurements of vocalization and language environment, including the true canonical babbling ratio and the infant-directed speech ratio, were analyzed for each time point of data collection for each infant. Statistical analyses were performed to conduct group and age comparisons for each measure of vocalization and language environment. Results No group differences emerged in number of syllables produced. Infants with CP exhibited late onset and fewer productions of canonical syllables compared to infants without CP. Infants with CP did not show significant differences from infants without CP in measures related to language environment across ages. Conclusion This study provides detailed information through naturalistic all-day home recordings about vocal development and early language environments in infants with CP before and after palatal repair. Clinical implications for early intervention are discussed.

Accurate reconstruction of the Late Cretaceous paleogeography and tectonic evolution of the western North American Cordilleran margin is required to resolve the long-standing debate over proposed large-scale, orogen-parallel terrane translation. The Nanaimo Basin (British Columbia, Canada) contains a high-fidelity record of orogenic exhumation and basin subsidence in the southwestern Canadian Cordillera that constrains the tectonic evolution of the region. Integration of detrital zircon U-Pb geochronology, conglomerate clast U-Pb geochronology, detrital muscovite 40Ar/39Ar thermochronology, and Lu-Hf isotopic analysis of detrital zircon defines a multidisciplinary provenance signature that provides a definitive linkage with sediment source regions north of the Sierra Nevada arc system (western United States).Analysis of spatial and temporal provenance variations within Nanaimo Group strata documents a bimodal sediment supply with a local source derived from the adjacent magmatic arc in the southern Coast Mountains batholith and an extra-regional source from the Mesoproterozoic Belt Supergroup and the Late Cretaceous Atlanta lobe of the Idaho batholith. Particularly robust linkages include: (1) juvenile (εHf >+10) Late Cretaceous zircon derived from the southern Coast Mountains batholith; (2) a bimodal Proterozoic detrital zircon signature consistent with derivation from Belt Supergroup (1700–1720 Ma) and ca. 1380 Ma plutonic rocks intruding the Lemhi subbasin of central Idaho (northwestern United States); (3) quartzite clasts that are statistical matches for Mesoproterozoic and Cambrian strata in Montana and Idaho (northwestern United States) and southern British Columbia; and (4) syndepositional evolved (εHf >−10) Late Cretaceous zircon and muscovite derived from the Atlanta lobe of the Idaho batholith. These provenance constraints support a tectonic restoration of the Nanaimo Basin, the southern Coast Mountains batholith, and Wrangellia to a position outboard of the Idaho batholith in Late Cretaceous time, consistent with proposed minimal- fault- offset models (

BackgroundAs the frequency of metallo-β-lactamase (MBL)-producing Enterobacterales is increasing worldwide, effective antimicrobials to treat the infections caused by these organisms are urgently needed.MethodsThe activity of aztreonam-avibactam and comparators were evaluated against 27 834 Enterobacterales isolates collected from 74 US medical centers in 2019–2021. Isolates were susceptibility tested by broth microdilution. An aztreonam-avibactam pharmacokinetic/pharmacodynamic breakpoint of ≤8 mg/L was applied for comparison. Antimicrobial susceptibility and the frequency of key resistance phenotypes were assessed then stratified by year and infection type. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing.ResultsAztreonam-avibactam inhibited >99.9% of Enterobacterales at ≤8 mg/L. Only 3 isolates (0.01%) had an aztreonam-avibactam minimum inhibitory concentration (MIC) >8 mg/L. The CRE rates were 0.8%, 0.9%, and 1.1% in 2019, 2020, and 2021, respectively; 99.6% (260 of 261) of CRE isolates were inhibited at an aztreonam-avibactam MIC of ≤8 mg/L. The CRE susceptibility to meropenem-vaborbactam decreased from 91.7% in 2019 to 83.1% in 2020 and 76.5% in 2021 (82.1% overall). The CRE, multidrug-resistant, and extensively drug-resistant phenotypes were markedly higher among isolates from pneumonia compared with other infections. The most common carbapenemase among CRE was Klebsiella pneumoniae carbapenemase (65.5% of CRE), followed by New Delhi metallo-β-lactamase (11.1%), oxacillinase (OXA)-48-like (4.6%), Serratia marcescens enzyme (2.3%), and imipenemase (1.5%). Among non-CPE-producing CRE isolates (n = 44; 16.9% of CRE), 97.7% were inhibited at ≤8 mg/L aztreonam-avibactam and 85.4% were meropenem-vaborbactam susceptible.ConclusionsThe frequencies of MBL and OXA-48-type producers increased markedly. Aztreonam-avibactam demonstrated potent and consistent activity against Enterobacterales across infection types and over time.

BackgroundThe temporal and longitudinal trends of β-lactamases and their associated susceptibility patterns were analyzed for Escherichia coli and Klebsiella pneumoniae isolates consecutively collected in 56 United States hospitals during 2016–2020.MethodsIsolates (n = 19 453) were susceptibility tested by reference broth microdilution methods. Isolates that displayed minimum inhibitory concentration (MIC) values ≥2 mg/L for at least 2 of the following compounds—ceftazidime, ceftriaxone, aztreonam, or cefepime—or resistance to the carbapenems were submitted to whole genome sequencing for identification of β-lactamases. Longitudinal and temporal trends were determined by slope coefficient. New CTX-M and OXA-1 variants were characterized.ResultsExtended-spectrum β-lactamases (ESBLs) were detected among 88.0% of the isolates that displayed elevated cephalosporin/aztreonam MICs without carbapenem resistance. blaCTX-M-15 was detected among 55.5% of the ESBL producers. ESBL rates were stable over time, but significant increases were noted among bloodstream infection and K pneumoniae isolates, mainly driven by an increase in blaCTX-M. Carbapenem resistance and carbapenemase genes were noted among 166 and 145 isolates, respectively, including 137 blaKPC, 6 blaSME, 3 blaOXA-48–like, and 3 blaNDM. Ceftazidime-avibactam and carbapenems were very active (>99% susceptibility) against ESBL producers without carbapenem resistance. Ceftazidime-avibactam inhibited 97.0% of the carbapenem-resistant isolates. This agent and meropenem-vaborbactam inhibited 96.4% and 85.0% of the 2020 isolates, respectively.ConclusionsOverall, ESBL-producing isolates were stable, but an increase was noted for K pneumoniae isolates driven by CTX-M production. Carbapenem-resistant Enterobacterales rates decreased in the study period. The prevalence of metallo-β-lactamases and OXA-48–like remains low. Continuous surveillance of β-lactamase–producing isolates is prudent.

Previous work has proposed that more frequent and more advanced child vocalizations may be a signal of increased fitness/well-being (see work by Locke and Oller – e.g., Locke, 2006 and Oller et al., 2019 – for additional background). However, this theoretical idea has not been tested empirically. This project will empirically test this, by studying the relationship between composite measures of child fitness/well-being and vocalization development in a sample of ~200 children from the Solomon Islands.

Protein synthesis by the ribosome involves large-scale rearrangements of the “small” subunit (SSU; ∼1 MDa), which include inter- and intra-subunit rotational motions. With more than 1000 structures of ribosomes and ribosomal subunits now publicly available, it is becoming increasingly difficult to design precise experiments that are based on a comprehensive analysis of all known rotation states. To overcome this limitation, we present the Ribosome Angle Decomposition (RAD) method, where the orientation of each small subunit head and body is described in terms of three angular coordinates (rotation, tilt and tilt direction) and a single translation. To demonstrate the utility of the accompanying software (RADtool) we applied it to all published ribosome and mitoribosome structures. This identified and analyzed 1077 fully-assembled ribosome complexes, as well as 280 isolated small subunits from 48 organisms. The RAD approach quantitatively distinguishes between previously described qualitative rotational features, determines when rotation-only descriptions are insufficient, and shows that tilt-like rearrangements of the SSU head and body are pervasive in both prokaryotic and eukaryotic ribosomes. Together, the presented database and technique provide a robust platform for systematically analyzing, visualizing, and comparing subunit orientations of ribosomes from all kingdoms of life. Accordingly, the RAD resource establishes a common foundation with which structural, simulation, single-molecule and biochemical efforts can precisely interrogate the dynamics of this prototypical molecular machine.

Background Gepotidacin is a novel first in class triazaacenaphthylene antibiotic in Phase 3 clinical trials for the treatment of gonorrhea and uncomplicated urinary tract infection (UTI). This study evaluates the epidemiology of E. coli (EC) causing UTI in US patients and the activity of gepotidacin and comparators against various subsets, including those with characterized resistance mechanisms. Methods 1,993 EC collected from 45 US sites were included as part of the Gepotidacin UTI Global Surveillance Study as part of the SENTRY Antimicrobial Surveillance Program (2019-2020). Isolates were tested for susceptibility (S) by CLSI methods and CLSI interpretations were applied. Isolates that met MIC criteria for screening of extended-spectrum β-lactamase (ESBL) genes were subjected to genome sequencing followed by ESBL gene screening and epidemiology typing (MLST, O:H, and fimH). Results A total of 84.4% (1,682/1,993) EC were ESBL negative (Table). Among these isolates, 16.5% (278/1,682) were not S to the fluoroquinolones (FQ) ciprofloxacin and/or levofloxacin, whereas 26.2% (440/1,682) were not S to trimethoprim-sulfamethoxazole (SXT). An ESBL phenotype was noted in 15.6% (311/1,993) of EC, which tended to be mostly not S to the FQs (79.7%), SXT (61.7%), amoxicillin-clavulanate (52.9%), and oral cephalosporins (99.7%). Most ESBL isolates carried CTX-M alleles alone (81.4%; 253/311), whereas 9.6% (30/311) had plasmid AmpC genes. Approximately half (56.3%; 175/311) of ESBL isolates belonged to clonal complex (CC) 131, of which 70.9% (124/175) were O25b:H4 and carried fimH30. Overall, gepotidacin had MIC90 of 2-4 mg/L against various phenotypic/genotypic subsets. Conclusion High rates of EC not S to commonly used oral agents (FQs and SXT) were observed. ESBL phenotype further compromised the activity of oral agents, including oral cephalosporins. Gepotidacin had potent and stable in vitro activity against various subsets, including the resistant CC131 O25b:H4 clone. These data support the further clinical development of gepotidacin as a treatment option for UTI caused by EC, including resistant isolates against which other oral treatment options are limited. Disclosures Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support SJ Ryan Arends, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Shionogi: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Nicole E. Scangarella-Oman, MS, GlaxoSmithKline plc.: Employee and shareholder Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

Background Cefiderocol (CFDC) is a siderophore cephalosporin that hijacks the Gram-negative bacteria iron transport system to facilitate cell entry and reach its target. CFDC remains stable to hydrolysis in the presence of serine β-lactamases (ESBLs, KPC, and OXA-type carbapenemases) and metallo-β-lactamases (MBL). CFDC and comparator activities were analyzed against Enterobacterales (ENT), including molecularly characterized isolates, as part of the SENTRY Antimicrobial Surveillance Program in the USA. Methods 8,328 ENT were collected from 32 sites in 2020-2021. Susceptibility testing was performed by broth microdilution. CFDC testing used iron-depleted media. CLSI breakpoints were used. E. coli, K. pneumoniae, and P. mirabilis with ceftriaxone, ceftazidime, or aztreonam MIC ≥2 μg/mL, and any ENT displaying MIC ≥2 μg/mL for imipenem (excluded for P. mirabilis, P. penneri, and indole-positive Proteeae) or meropenem (MER), were subjected to genome sequencing and screening of β-lactamase genes. Results In general, CFDC (≥ 99.9% susceptible [S]), imipenem-relebactam (IMR; 99.4-100%S), meropenem-vaborbactam (MEV; 100%S), and ceftazidime-avibactam (CZA; 100%S) were active against carbapenem-susceptible ENT that carried ESBL and/or AmpC genes (Table). CFDC (MIC50/90, 0.5/4 μg/mL; 98.4%S) and CZA (MIC50/90, 1/8 μg/mL; 91.2%S) were the most active agents against carbapenem-nonS isolates, whereas IMR (MIC50/90, 0.25/4 μg/mL; 81.6%S) and MEV (MIC50/90, 0.12/8 μg/mL; 86.4%S) had suboptimal activity. CFDC (MIC50/90, 0.5/2 μg/mL), IMR (MIC50/90, 0.12/0.5 μg/mL), MEV (MIC50/90, 0.03/0.5 μg/mL), and CZA (MIC50/90, 1/2 μg/mL) were active (100%S) against the KPC subset. CFDC (MIC, 0.5-4 μg/mL; 100%S) was also active against ENT carrying MBL genes, whereas CFDC (MIC, 0.5-2 μg/mL; 100%S) and CZA (1-4 μg/mL; 100%S) were active against isolates carrying blaOXA-48-like. Conclusion CFDC activity was consistent, regardless of phenotypes or genotypes, including against isolates carrying carbapenemase genes other than blaKPC, where approved β-lactam/β-lactamase inhibitor combinations showed limited activity. These data reinforce CFDC as an important option for the treatment of infections caused by ENT and resistant subsets. Disclosures Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support John H. Kimbrough, PhD, AbbVie: Grant/Research Support|GSK: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

The present work examined canonical babbling ratios longitudinally as a measure of onset and consolidation of canonical babbling in two infants at risk of cerebral palsy (CP) between 5 and 16 months. Ten typically developing infants were included for comparison at 6, 9, 12, and 16–19 months. Canonical babbling ratios (CBRs) were calculated from 5-min segments, and follow-up diagnostic outcomes were collected between 24 and 33 months. The two infants at risk demonstrated low CBR growth trajectories compared to the typical infant group, and slightly different patterns of consolidation. The two infants at risk were later diagnosed with different levels of CP and speech impairment severity. All infants demonstrated greater variability than expected. Studying canonical babbling and other prelinguistic milestones in this population may inform our perspective of the involvement of the motor system in the vocal domain. Additional implications on the analysis of canonical babbling using all-day home recordings are discussed.

Additional co-authors: Ivan Ropovik, Balazs Aczel, Lena F. Aeschbach, Luca Andrighetto, Jack D. Arnal, Holly Arrow, Peter Babincak, Bence E. Bakos, Gabriel Banik, Ernest Baskin, Radomir Belopavlovic, Michael H. Bernstein, Michal Bialek, Nicholas G. Bloxsom, Bojana Bodroža, Diane B. V. Bonfiglio, Leanne Boucher, Florian Bruhlmann, Claudia C. Brumbaugh, Erica Casini, Yiling Chen, Carlo Chiorri, William J. Chopik, Oliver Christ, Antonia M. Ciunci, Heather M. Claypool, Sean Coary, Marija V. Cˇolic, W. Matthew Collins, Paul G. Curran, Chris R. Day, Anna Dreber, John E. Edlund, Filipe Falcao, Anna Fedor, Lily Feinberg, Ian R. Ferguson, Maire Ford, Michael C. Frank, Emily Fryberger, Alexander Garinther, Katarzyna Gawryluk, Kayla Ashbaugh, Mauro Giacomantonio, Steffen R. Giessner, Jon E. Grahe, Rosanna E. Guadagno, Ewa Halasa, Rias A. Hilliard, Joachim Huffmeier, Sean Hughes, Katarzyna Idzikowska, Michael Inzlicht, Alan Jern, William Jimenez-Leal, Magnus Johannesson, Jennifer A. Joy-Gaba, Mathias Kauff, Danielle J. Kellier, Grecia Kessinger, Mallory C. Kidwell, Amanda M. Kimbrough, Josiah P. J. King, Vanessa S. Kolb, Sabina Kolodziej, Marton Kovacs, Karolina Krasuska, Sue Kraus, Lacy E. Krueger, Katarzyna Kuchno, Caio Ambrosio Lage, Eleanor V. Langford, Carmel A. Levitan, Tiago Jesse Souza de Lima, Hause Lin, Samuel Lins, Jia E. Loy, Dylan Manfredi, Łukasz Markiewicz, Madhavi Menon, Brett Mercier, Mitchell Metzger, Venus Meyet, Jeremy K. Miller, Andres Montealegre, Don A. Moore, Rafal Muda, Gideon Nave, Austin Lee Nichols, Sarah A. Novak, Christian Nunnally, Ana Orlic, Anna Palinkas, Angelo Panno, Kimberly P. Parks, Ivana Pedovic, Emilian Pekala, Matthew R. Penner, Sebastiaan Pessers, Boban Petrovic, Thomas Pfeiffer, Damian Pienkosz, Emanuele Preti, Danka Puric, Tiago Ramos, Jonathan Ravid, Timothy S. Razza, Katrin Rentzsch, Juliette Richetin, Sean C. Rife, Anna Dalla Rosa, Kaylis Hase Rudy, Janos Salamon, Blair Saunders, Przemyslaw Sawicki, Kathleen Schmidt, Kurt Schuepfer, Thomas Schultze, Stefan Schulz-Hardt, Astrid Schutz, Ani N. Shabazian, Rachel L. Shubella, Adam Siegel, Ruben Silva, Barbara Sioma, Lauren Skorb, Luana Elayne Cunha de Souza, Sara Steegen, L. A. R. Stein, R. Weylin Sternglanz, Darko Stojilovic, Daniel Storage, Gavin Brent Sullivan, Barnabas Szaszi, Peter Szecsi, Orsolya Szoke, Attila Szuts, Manuela Thomae, Natasha D. Tidwell, Carly Tocco, Ann-Kathrin Torka, Francis Tuerlinckx, Wolf Vanpaemel, Leigh Ann Vaughn, Michelangelo Vianello, Domenico Viganola, Maria Vlachou, Ryan J. Walker, Sophia C. Weissgerber, Aaron L. Wichman, Bradford J. Wiggins, Daniel Wolf, Michael J. Wood, David Zealley, Iris Žeželj, Mark Zrubka, and Brian A. Nosek